Combination of a Dipeptidyl Peptidase-IV Inhibitor and a Cannabinoid CB1 Receptor Antagonist for the Treatment of Diabetes and Obesity

ABSTRACT

The present invention relates to pharmaceutical compositions comprising a combination of a particular dipeptidyl peptidase-IV (DPP-IV) inhibitor and a particular cannabinoid CB?1#191 receptor antagonist/inverse agonist, kits containing such combinations and methods of using such compositions for the treatment of diabetes, diabetes associated with obesity, diabetes-related disorders, obesity, and obesity-related disorders.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions comprisinga combination of a particular dipeptidyl peptidase-IV (DPP-IV) inhibitorand a particular cannabinoid CB₁ receptor antagonist/inverse agonist,kits containing such combinations and methods of using such compositionsfor the treatment of diabetes, diabetes associated with obesity,diabetes-related disorders, obesity, and obesity-related disorders.

BACKGROUND OF THE INVENTION

Diabetes is caused by multiple factors and is most simply characterizedby elevated levels of plasma glucose (hyperglycemia) in the fasting orpost glucose-challenge state. There are two generally recognized formsof diabetes: Type 1 diabetes, or insulin-dependent diabetes mellitus(IDDM), in which patients produce little or no insulin, the hormonewhich regulates glucose utilization, and Type 2 diabetes, ornoninsulin-dependent diabetes mellitus (NIDDM), wherein patients producesome insulin and even exhibit hyperinsulinemia (plasma insulin levelsthat are the same or even elevated in comparison with non-diabeticsubjects), while at the same time demonstrating hyperglycemia. Type 1diabetes is typically treated with exogenous insulin administered viainjection. However, Type 2 diabetics often develop “insulin resistance”,such that the effect of insulin in stimulating glucose and lipidmetabolism in the main insulin-sensitive tissues, namely, muscle, liverand adipose tissues, is diminished. Patients who are insulin resistantbut not diabetic may have elevated insulin levels that compensate fortheir insulin resistance, so that serum glucose levels are not elevated.In patients with Type 2 diabetes, the plasma insulin levels, even whenthey are elevated, are insufficient to overcome the pronounced insulinresistance, resulting in hyperglycemia.

Insulin resistance is primarily due to a post receptor signaling defectthat is not yet completely understood. Resistance to insulin results ininsufficient activation of glucose uptake, diminished oxidation ofglucose and storage of glycogen in muscle, inadequate insulin repressionof lipolysis in adipose tissue and inadequate suppression of glucoseproduction by the liver.

The persistent or uncontrolled hyperglycemia that occurs in diabetics isassociated with increased morbidity and premature mortality. Type 2diabetics are at increased risk of developing cardiovascularcomplications, e.g., atherosclerosis, coronary heart disease, stroke,peripheral vascular disease, hypertension, nephropathy, neuropathy, andretinopathy.

Many patients who have insulin resistance but have not yet developedType 2 diabetes are also at a risk of developing Metabolic Syndrome,also referred to as syndrome X, insulin resistance syndrome, orpluriMetabolic Syndrome. The period of 5 to 10 years preceding thedevelopment of impaired glucose tolerance is associated with a number ofhormonal imbalances, which give rise to an enlargement of visceral fatmass, hypertension, insulin resistance, and hyperlipidemia (Bjornstop,P., Current Topics in Diabetes Research, eds. Belfore, F., Bergman, R.N., and Molinath, G. M., Front Diabetes, Basel, Karger, 12: 182-192(1993)). Similarly, Metabolic Syndrome is characterized by insulinresistance, along with abdominal obesity, hyperinsulinemia, high bloodpressure, low HDL and high VLDL. Although the causal relationshipbetween the various components of Metabolic Syndrome remains to beconfirmed, insulin resistance or abdominal obesity appears to play animportant role (Requen, G. M., et al., N. Eng. J. Med., 334: 374-381(1996); Despres, J-P., et al., N. Engl. J. Med., 334: 952-957 (1996);Wajchenberg, B. L., et al., Diabetes/Metabolism Rev., 10: 19-29 (1994)).Metabolic Syndrome patients, whether or not they develop overt diabetesmellitus, are at increased risk of developing the cardiovascularcomplications listed above. Diabetes can be treated with a variety oftherapeutic agents, including insulin sensitizers, such as PPARγagonists, such as glitazones and glitazars; biguanides; protein tyrosinephosphatase-1B inhibitors; dipeptidyl peptidase-IV inhibitors; insulin;insulin mimetics; sulfonylureas; meglitinides; α-glucosidase inhibitors;and α-amylase inhibitors.

Increasing the plasma level of insulin by administration ofsulfonylureas (e.g. tolbutamide and glipizide) or meglitinides, whichstimulate the pancreatic β-cells to secrete more insulin, and/or byinjection of insulin when sulfonylureas or meglitinides becomeineffective, can result in insulin concentrations high enough tostimulate insulin-resistant tissues. However, dangerously low levels ofplasma glucose can result, and increasing insulin resistance due to theeven higher plasma insulin levels can occur. The biguanides have anunknown mechanism of action but decrease hepatic glucose output andincrease insulin sensitivity resulting in some correction ofhyperglycemia. Metformin monotherapy is often used for treating Type 2diabetic patients who are also obese and/or dyslipidernic. Lack ofappropriate response to metformin is often followed by treatment withsulfonylureas, thiazolidinediones, insulin, or α-glucosidase inhibitors.However, the two biguanides, phenformin and metformin, can also inducelactic acidosis and nausea/diarrhea, respectively. α-Glucosidaseinhibitors, such as acarbose, work by delaying absorption of glucose inthe intestine. α-Amylase inhibitors inhibit the enzymatic degradation ofstarch or glycogen into maltose, which also reduces the amounts ofbioavailable sugars.

The PPAR-γ agonists, including glitazones, also known asthiazolidinediones (i.e. 5-benzylthiazolidine-2,4-diones) andnon-thiazolidinediones, i.e. glitizars, represent another class ofcompounds with potential for ameliorating many symptoms of Type 2diabetes. These agents substantially increase insulin sensitivity inmuscle, liver and adipose tissue in several animal models of Type 2diabetes resulting in partial or complete correction of the elevatedplasma levels of glucose without occurrence of hypoglycemia. Theglitazones that are currently marketed are agonists of the peroxisomeproliferator activated receptor (PPAR) gamma subtype. PPAR-gamma agonismis generally believed to be responsible for the improved insulinsensitization that is observed with the glitazones. Newer PPAR agoniststhat are being developed for treatment of Type 2 diabetes and/ordyslipidemia are agonists of one or more of the PPAR alpha, gamma anddelta subtypes.

However, treatment of diabetes with PPARγ agonists has been associatedwith fluid retention. Recent labeling revisions for Avandia®(rosiglitazone maleate), a PPARγ agonist, indicate that patients mayexperience fluid accumulation and volume-related events such as edemaand congestive heart failure.

Treatment of Type 2 diabetes also typically includes physical exercise,weight control, and dieting. While physical exercise and reductions indietary intake of calories will dramatically improve the diabeticcondition, compliance with this treatment is very poor because ofwell-entrenched sedentary lifestyles and excess food consumption,especially of foods containing high amounts of saturated fat. However,weight reduction and increased exercise are difficult for most peoplewith diabetes.

Abnormal glucose homeostasis is also associated both directly andindirectly with obesity, hypertension and alterations in lipid,lipoprotein and apolipoprotein metabolism. Obesity increases thelikelihood of insulin resistance, and increases the likelihood that theresulting insulin resistance will increase with increasing body weight.Therefore, therapeutic control of glucose homeostasis, lipid metabolism,obesity and hypertension are critically important in the prevention ofand clinical management and treatment of diabetes mellitus.

Obesity, which can be defined as a BMI>30 kg/m2 for Caucasians or >25kg/m2 for Asians, is a major health concern in Western societies. It isestimated that about 97 million adults in the United States areoverweight or obese. Obesity is the result of a positive energy balance,as a consequence of increased ratio of caloric intake to energyexpenditure. The molecular factors regulating food intake and bodyweight balance are incompletely understood [B. Staels et al., J. Biol.Chem., 270: 15958 (1995); F. Lonnquist et al., Nature Medicine, 1: 950(1995)]. Although the genetic and/or environmental factors leading toobesity are poorly understood, several genetic factors have beenidentified.

Epidemiological studies have shown that increasing degrees of overweightand obesity are important predictors of decreased life expectancy.Obesity causes or exacerbates many health problems, both independentlyand in association with other diseases. The medical problems associatedwith obesity, which can be serious and life-threatening, include Type 2diabetes mellitus; hypertension; elevated plasma insulin concentrations;insulin resistance; dyslipidemias; hyperlipidemia; endometrial, breast,prostate, kidney and colon cancer; osteoarthritis; respiratorycomplications, such as obstructive sleep apnea; gallstones;atherosclerosis; heart disease; abnormal heart rhythms; and heartarrythmias (Kopelman, P. G., Nature, 404: 635-643 (2000)). Obesity isalso associated with Metabolic Syndrome, cardiac hypertrophy, inparticular left ventricular hypertrophy, premature death, and with asignificant increase in mortality and morbidity from stroke, myocardialinfarction, congestive heart failure, coronary heart disease, and suddendeath.

Abdominal obesity has been linked with a much higher risk of coronaryartery disease, and with three of its major risk factors: high bloodpressure, diabetes that starts in adulthood, and high levels of fats(lipids) in the blood. Losing weight dramatically reduces these risks.Abdominal obesity is further closely associated with glucoseintolerance, hyperinsulinemia, hypertriglyceridemia, and other disordersassociated with Metabolic Syndrome, such as raised high blood pressure,decreased levels of high density lipoproteins (HDL) and increased levelsof very low density lipoproteins (VLDL) (Montague et al., Diabetes, 49:883-888 (2000)).

Obesity and obesity-related disorders, such as diabetes, are oftentreated by encouraging patients to lose weight by reducing their foodintake or by increasing their exercise level, thereby increasing theirenergy output. A sustained weight loss of 5% to 10% of body weight hasbeen shown to improve the co-morbidities associated with obesity, suchas diabetes, and can lead to improvement of obesity-related disorders,such as left ventricular hypertrophy, osteoarthritis, and pulmonary andcardiac dysfunction.

Weight loss drugs used for the treatment of obesity include orlistat[Davidson, M. H. et al., JAMA. 281: 235-42 (1999)], dexfenfluramine [GuyGrand, B. et al., Lancet. 2: 1142-5 (1989)], sibutramine [Bray, G. A. etal., Obes. Res., 7: 189-98 (1999)], and phentermine [Douglas, A. et al.,Int. J. Obes., 7: 591-5 (1983)]. However, the side effects of thesedrugs and anti-obesity agents may limit their use. Dexfenfluramine waswithdrawn from the market because of suspected heart valvulopathy;orlistat is limited by gastrointestinal side effects; and the use ofsibutramine is limited by its cardiovascular side effects which have ledto reports of deaths and its withdrawal from the market in Italy.

There is a continuing need for new methods of treating diabetes,diabetes associated with obesity, and diabetes-related disorders. Thereis also a need for new methods of treating and preventing obesity andobesity related disorders, such as Metabolic Syndrome. There iscurrently no approved treatment for Metabolic Syndrome.

The present invention addresses this problem by providing a combinationtherapy comprising of a particular dipeptidyl peptidase-IV (DPP-IV)inhibitor and a particular cannabinoid CB₁ antagonist/inverse agonistfor the treatment of diabetes, diabetes associated with obesity,diabetes-related disorders, obesity, and obesity-related disorders. Thecombination of these agents, at their respective clinical doses, isexpected to be more effective than treatment with either agent alone.Treatment with such a combination at sub-clinical doses is expected toproduce clinical efficacy with fewer side effects than treatment witheither single agent at the monotherapy clinical dose. As a result,combination therapy is more likely to achieve the desired medicalbenefits without the trial and error involved in prescribing each agentindividually during primary care.

SUMMARY OF THE INVENTION

The present invention provides compositions comprising an anti-obesityagent which is a particular cannabinoid CB₁ receptor antagonist/inverseagonist and an anti-diabetic agent which is a particular DPP-IVinhibitor, which compositions are useful in the treatment, controland/or prevention of diabetes, diabetes associated with obesity,diabetes-related disorders, obesity, and obesity-related disorders.

The therapeutic utility of DPP-IV inhibitors for the treatment of Type 2diabetes is discussed by (i) D. J. Drucker in Exp. Opin. Invest. Drugs.12: 87-100 (2003); (ii) K. Augustyns, et al., in Exp. Opin. Ther.Patents, 13: 499-510 (2003); (iii) C. F. Deacon, et al., in Exp. Opin.Investig. Drugs, 13: 1091-1102 (2004); (iv) A. E. Weber, “DipeptidylPeptidase IV Inhibitors for the Treatment of Diabetes,” J. Med. Chem.,47: 4135-4141 (2004); and (v) J. J. Holst, “Treatment of Type 2 diabetesmellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors,” Exp.Opin. Emerg. Drugs, 9: 155-166 (2004).

The therapeutic effects of cannabinoid receptor ligands has beendescribed in (i) R. G. Pertwee, “Cannabinoid receptor ligands: clinicaland neuropharmacological considerations, relevant to future drugdiscovery and development, Exp. Opin. Invest. Drugs, 9: 1553-1571 (2000)and (ii) A. J. Drysdale, “Cannibinoids: Mechanisms and TherapeuticApplications in the CNS,” Curr. Med. Chem., 10: 2719-2732 (2003).

The compositions of the present invention are useful in the treatment,control and/or prevention of diabetes, in particular Type 2 diabetes, inhumans.

The compositions of the present invention are further useful in thetreatment, control and/or prevention of hyperlipidemia; dyslipidemia;obesity; abdominal obesity; hypercholesterolemia; hypertrigyceridemia;atherosclerosis; coronary heart disease; stroke; hypertension;peripheral vascular disease; vascular restenosis; nephropathy;neuropathy; inflammatory conditions, such as, but not limited to,irritable bowel syndrome, inflammatory bowel disease, including Crohn'sdisease and ulcerative colitis; other inflammatory conditions;pancreatitis; neurodegenerative disease; retinopathy; neoplasticconditions, such as, but not limited to adipose cell tumors, adiposecell carcinomas, such as liposarcoma; cancers, including gastric andbladder cancers; angiogenesis; Alzheimer's disease; psoriasis; and otherdisorders where insulin resistance is a component.

The compositions of the present invention are also useful in thetreatment, control and/or prevention of overeating; bulimia; elevatedplasma insulin concentrations; insulin resistance; glucose tolerance;lipid disorders; low HDL levels; high LDL levels; hyperglycemia;neoplastic conditions, such as endometrial, breast, prostate, kidney andcolon cancer; osteoarthritis; obstructive sleep apnea; gallstones;abnormal heart rhythms; heart arrythmias; myocardial infarction;congestive heart failure; sudden death; ovarian hyperandrogenism,(polycystic ovary disease); craniopharyngioma; the Prader-WilliSyndrome; Frohlich's syndrome; GH-deficient subjects; normal variantshort stature; Turner's syndrome; and other pathological conditionsshowing reduced metabolic activity or a decrease in resting energyexpenditure as a percentage of total fat-free mass, e.g, children withacute lymphoblastic leukemia.

The compositions of the present invention are also useful in thetreatment, control, and/or prevention of diabetes while mitigatingcardiac hypertrophy, including left ventricular hypertrophy.

The compositions of the present invention are further useful in thetreatment, control, and/or prevention of Metabolic Syndrome.

The present invention is also concerned with treatment of theseconditions, and the use of the compositions of the present invention forthe manufacture of a medicament useful for treating these conditions.

The invention is also concerned with pharmaceutical compositionscomprising a particular DPP-IV inhibitor and a particular cannabinoidCB₁ receptor antagonist/inverse agonist as active pharmaceuticalingredients.

The present invention is also concerned with the use of a particularDPP-IV inhibitor and a particular cannabinoid CB₁ receptorantagonist/inverse agonist, for the manufacture of a medicament for thetreatment of diabetes, diabetes associated with obesity,diabetes-related disorders, obesity, and obesity-related disorders,which comprises a therapeutically effective amount of such DPP-IVinhibitor and such cannabinoid CB₁ receptor antagonist/inverse agonist,together or separately.

The present invention is also concerned with a drug product containing aparticular DPP-IV inhibitor and a particular cannabinoid CB₁ receptorantagonist/inverse agonist, as a combined preparation for simultaneous,separate or sequential use in diabetes, diabetes associated withobesity, diabetes-related disorders, obesity, and obesity-relateddisorders.

The present invention also relates to the treatment of diabetes,diabetes associated with obesity, diabetes-related disorders, obesity,and obesity-related disorders with a combination of a particular DPP-IVinhibitor and a particular cannabinoid CB₁ receptor antagonist/inverseagonist, which may be administered separately.

The invention also relates to combining separate pharmaceuticalcombinations into a kit form.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compositions comprising an anti-obesityagent which is a particular cannabinoid CB₁ receptor antagonist/inverseagonist and an anti-diabetic agent which is a particular DPP-IVinhibitor which compositions are useful in the treatment or preventionof diabetes, diabetes associated with obesity, diabetes-relateddisorders, obesity, and obesity-related disorders.

The cannabinoid CB₁ receptor antagonist/inverse agonists used in thecompositions of the present invention are selected from the groupconsisting of:

-   N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;-   N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;-   N-[3-(4-chlorophenyl)-1-methyl-2-phenyl-propyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;-   N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   N-[3-(4-chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide;-   N-[3-(4-chlorophenyl)-1-methyl-2-(thiophen-3-yl)propyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;-   N-[3-(5-chloro-2-pyridyl)-2-phenyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   N-[3-(4-fluorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   N-[3-(4-methoxy-phenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;-   N-[2-(3-cyanophenyl)-1,4-dimethylpentyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   N-[2-(3-cyanophenyl)-3-cyclobutyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   N-[2-(3-cyanophenyl)-1-methyl-heptyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   N-[2-(3-cyanophenyl)-3-cyclopentyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   N-[2-(3-cyanophenyl)-3-cyclohexyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;-   3-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-3-(3,5-difluorophenyl)-2,2-dimethylpropanenitrile;-   1-{1-[1-(4-chlorophenyl)pentyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol;-   3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile;-   3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile;-   3-((4-chlorophenyl){3-[1-(3,5-difluorophenyl)-2,2-dimethylpropyl]azetidin-1-yl}methyl)benzonitrile;-   3-((1S)-1-{1-[(S)-3-cyanophenyl)(4-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile;-   3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-4H-1,2,4-triazol-4-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile;    and-   5-((4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)thiophene-3-carbonitrile;    and stereoisomers, pharmaceutically acceptable salts, hydrates, and    crystalline forms thereof.

The above cannabinoid CB₁ receptor antagonist/inverse agonists aredisclosed in international patent publication WO 2003/077847 (published24 Sep. 2003) and international patent publication WO 2005/000809(published 6 Jan. 2005).

In one embodiment the cannabinoid CB₁ receptor antagonist/inverseagonist isN-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamideof structural formula III:

or a pharmaceutically acceptable salt, hydrate, or crystalline formthereof.

The methods and compositions of the present invention also comprise ananti-diabetic agent which is a particular DPP-IV inhibitor selected fromthe group consisting of:

and pharmaceutically acceptable salts, hydrates, and crystalline formsthereof.

In one embodiment the particular DPP-IV inhibitor is(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3α]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amineof structural formula IV:

or a pharmaceutically acceptable salt, hydrate, or crystalline formthereof.

In a class of this embodiment the pharmaceutically acceptable salt ofthe compound of formula IV is the dihydrogenphosphate salt of structuralformula V:

or a pharmaceutically acceptable hydrate thereof. In a subclass of thisclass the pharmaceutically acceptable hydrate is a crystallinemonohydrate. The crystalline dihydrogenphosphate monohydrate is referredto as MK-0431.

The DPP-IV inhibitors in the compositions of the present invention aredisclosed in U.S. Pat. No. 6,699,871 (Mar. 2, 2004), the contents ofwhich are incorporated herein by reference in their entirety. Thedevelopment of this series of DPP-IV inhibitors has been described by D.Kim, et al., in J. Med. Chem., 48: 141-151 (2005).

The present invention also relates to a method of treating, controlling,or preventing diabetes, particularly non-insulin dependent diabetesmellitus, comprising administering to a subject in need thereof:

(a) a therapeutically or prophylactically effective amount of aparticular cannabinoid CB₁ receptor antagonist/inverse agonist, or apharmaceutically acceptable salt thereof; and(b) a therapeutically or prophylactically effective amount of aparticular DPP-IV inhibitor, or a pharmaceutically acceptable saltthereof.

The present invention relates to a method of treating, controlling, orpreventing diabetes associated with obesity comprising administering toa subject in need thereof:

(a) a therapeutically or prophylactically effective amount of aparticular cannabinoid CB₁ receptor antagonist/inverse agonist, or apharmaceutically acceptable salt thereof; and(b) a therapeutically or prophylactically effective amount of aparticular DPP-IV inhibitor, or a pharmaceutically acceptable saltthereof.

The present invention relates to a method of treating, controlling, orpreventing hypercholesterolemia, atherosclerosis, low HDL levels, highLDL levels, hyperlipidemia, hypertriglyceridemia, and/or dyslipidemia,comprising administering to a subject in need thereof:

(a) a therapeutically or prophylactically effective amount of aparticular cannabinoid CB₁ receptor antagonist/inverse agonist, or apharmaceutically acceptable salt thereof; and(b) a therapeutically or prophylactically effective amount of aparticular DPP-IV inhibitor, or a pharmaceutically acceptable saltthereof.

The present invention relates to a method of treating, controlling, orpreventing hyperglycemia comprising administering to a subject in needthereof:

(a) a therapeutically or prophylactically effective amount of aparticular cannabinoid CB₁ receptor antagonist/inverse agonist, or apharmaceutically acceptable salt thereof; and(b) a therapeutically or prophylactically effective amount of aparticular DPP-IV inhibitor, or a pharmaceutically acceptable saltthereof.

The present invention relates to a method of treating, controlling, orpreventing hypercholesterolemia comprising administering to a subject inneed thereof:

(a) a therapeutically or prophylactically effective amount of aparticular cannabinoid CB₁ receptor antagonist/inverse agonist, or apharmaceutically acceptable salt thereof; and(b) a therapeutically or prophylactically effective amount of aparticular DPP-IV inhibitor, or a pharmaceutically acceptable saltthereof.

The present invention relates to a method of treating, controlling, orpreventing hypertriglyceridemia comprising administering to a subject inneed thereof:

(a) a therapeutically or prophylactically effective amount of aparticular cannabinoid CB₁ receptor antagonist/inverse agonist, or apharmaceutically acceptable salt thereof; and(b) a therapeutically or prophylactically effective amount of aparticular DPP-IV inhibitor, or a pharmaceutically acceptable saltthereof.

The present invention relates to a method of treating, controlling, orpreventing lipid disorders, hyperlipidemia, dyslipidemia, high non-HDLcholesterol, and low-HDL cholesterol comprising administering to asubject in need thereof:

(a) a therapeutically or prophylactically effective amount of aparticular cannabinoid CB₁ receptor antagonist/inverse agonist, or apharmaceutically acceptable salt thereof; and(b) a therapeutically or prophylactically effective amount of aparticular DPP-IV inhibitor, or a pharmaceutically acceptable saltthereof.

The present invention relates to a method of treating, controlling, orpreventing dyslipidemia, including low HDL cholesterol comprisingadministering to a subject in need thereof:

(a) a therapeutically or prophylactically effective amount of aparticular cannabinoid CB₁ receptor antagonist/inverse agonist, or apharmaceutically acceptable salt thereof; and(b) a therapeutically or prophylactically effective amount of aparticular DPP-IV inhibitor, or a pharmaceutically acceptable saltthereof.

The present invention relates to a method of treating, controlling, orpreventing atherosclerosis comprising administering to a subject in needthereof:

(a) a therapeutically or prophylactically effective amount of aparticular cannabinoid CB₁ receptor antagonist/inverse agonist, or apharmaceutically acceptable salt thereof; and(b) a therapeutically or prophylactically effective amount of aparticular DPP-IV inhibitor, or a pharmaceutically acceptable saltthereof.

It is understood that the sequellae of atherosclerosis (angina,claudication, heart attack, stroke, etc.) are thereby treated.

The present invention relates to a method of treating, controlling, orpreventing diabetes while mitigating cardiac hypertrophy, particularlyleft ventricular hypertrophy, comprising administering to a subject inneed thereof:

(a) a therapeutically or prophylactically effective amount of aparticular cannabinoid CB₁ receptor antagonist/inverse agonist, or apharmaceutically acceptable salt thereof; and(b) a therapeutically or prophylactically effective amount of aparticular DPP-IV inhibitor, or a pharmaceutically acceptable saltthereof.

The present invention relates to a method of treating, controlling, orpreventing Metabolic Syndrome comprising administering to a subject inneed thereof:

(a) a therapeutically or prophylactically effective amount of aparticular cannabinoid CB₁ receptor antagonist/inverse agonist, or apharmaceutically acceptable salt thereof; and(b) a therapeutically or prophylactically effective amount of aparticular DPP-IV inhibitor, or a pharmaceutically acceptable saltthereof.

The present invention relates to a method of treating a diabetes-relateddisorder comprising administering to a subject in need thereof:

(a) a therapeutically effective amount of a particular cannabinoid CB₁receptor antagonist/inverse agonist, or a pharmaceutically acceptablesalt thereof; and(b) a therapeutically effective amount of a particular DPP-IV inhibitor,or a pharmaceutically acceptable salt thereof.

The present invention relates to a method of treating or preventingobesity comprising administering to a subject in need thereof:

(a) a therapeutically or prophylactically effective amount of aparticular cannabinoid CB₁ receptor antagonist/inverse agonist, or apharmaceutically acceptable salt thereof; and(b) a therapeutically or prophylactically effective amount of aparticular DPP-IV inhibitor, or a pharmaceutically acceptable saltthereof.

The present invention relates to a method of treating or preventing anobesity-related disorder comprising administering to a subject in needthereof:

(a) a therapeutically or prophylactically effective amount of aparticular cannabinoid CB₁ receptor antagonist/inverse agonist, or apharmaceutically acceptable salt thereof; and(b) a therapeutically or prophylactically effective amount of aparticular DPP-IV inhibitor, or a pharmaceutically acceptable saltthereof.

The present invention also relates to pharmaceutical compositions andmedicaments useful for carrying out these methods.

The present invention relates to the use of an anti-obesity agent whichis a particular cannabinoid CB₁ receptor antagonist/inverse agonist, ora pharmaceutically acceptable salt, hydrate, or crystalline formthereof; and an anti-diabetic agent which is a particular DPP-IVinhibitor, or a pharmaceutically acceptable salt, hydrate, orcrystalline form thereof; for the manufacture of a medicament fortreatment, control, or prevention of diabetes which comprises aneffective amount of such anti-obesity agent and an effective amount ofsuch anti-diabetic agent, together or separately.

The present invention also relates to the use of an anti-obesity agentwhich is a particular cannabinoid CB₁ receptor antagonist/inverseagonist, or a pharmaceutically acceptable salt, hydrate, or crystallineform thereof; and an anti-diabetic agent which is a particular DPP-IVinhibitor, or a pharmaceutically acceptable salt, hydrate, orcrystalline form thereof; for the manufacture of a medicament fortreatment, control, or prevention of diabetes associated with obesitywhich comprises a therapeutically or prophylactically effective amountof such anti-obesity agent and an effective amount of such anti-diabeticagent, together or separately.

The present invention relates to the use of an anti-obesity agent whichis a particular cannabinoid CB₁ receptor antagonist/inverse agonist, ora pharmaceutically acceptable salt, hydrate, or crystalline formthereof; and an anti-diabetic agent which is a particular DPP-IVinhibitor, or a pharmaceutically acceptable salt, hydrate, orcrystalline form thereof; for the manufacture of a medicament fortreatment, control, or prevention of a diabetes-related disorder whichcomprises a therapeutically or prophylactically effective amount of suchanti-obesity agent and an effective amount of such anti-diabetic agent,together or separately.

The present invention relates to the use of an anti-obesity agent whichis a particular cannabinoid CB₁ receptor antagonist/inverse agonist, ora pharmaceutically acceptable salt, hydrate, or crystalline formthereof; and an anti-diabetic agent which is a particular DPP-IVinhibitor, or a pharmaceutically acceptable salt, hydrate, orcrystalline form thereof; for the manufacture of a medicament fortreatment, control, or prevention of obesity which comprises atherapeutically or prophylactically effective amount of suchanti-obesity agent and an effective amount of such anti-diabetic agent,together or separately.

The present invention relates to the use of an anti-obesity agent whichis a particular cannabinoid CB₁ receptor antagonist/inverse agonist, ora pharmaceutically acceptable salt, hydrate, or crystalline formthereof; and an anti-diabetic agent which is a particular DPP-IVinhibitor, or a pharmaceutically acceptable salt, hydrate, orcrystalline form thereof; for the manufacture of a medicament fortreatment, control, or prevention of an obesity-related disorder whichcomprises a therapeutically or prophylactically effective amount of suchanti-obesity agent and an effective amount of such anti-diabetic agent,together or separately.

The present invention relates to the use of an anti-obesity agent whichis a particular cannabinoid CB₁ receptor antagonist/inverse agonist, ora pharmaceutically acceptable salt, hydrate, or crystalline formthereof; and an anti-diabetic agent which is a particular DPP-IVinhibitor, or a pharmaceutically acceptable salt, hydrate, orcrystalline form thereof; for the manufacture of a medicament fortreatment, control, or prevention of Metabolic Syndrome which comprisesa therapeutically or prophylactically effective amount of suchanti-obesity agent and an effective amount of such anti-diabetic agent,together or separately.

The present invention relates to the use of an anti-obesity agent whichis a particular cannabinoid CB₁ receptor antagonist/inverse agonist, ora pharmaceutically acceptable salt, hydrate, or crystalline formthereof; and an anti-diabetic agent which is a particular DPP-IVinhibitor, or a pharmaceutically acceptable salt, hydrate, orcrystalline form thereof; for the manufacture of a medicament fortreatment, control, or prevention of diabetes while mitigating cardiachypertrophy, particularly left ventricular hypertrophy, which comprisesa therapeutically or prophylactically effective amount of suchanti-obesity agent and a therapeutically or prophylactically effectiveamount of such anti-diabetic agent, together or separately.

The present invention further relates to a drug product containing ananti-obesity agent which is a particular cannabinoid CB₁ receptorantagonist/inverse agonist, or a pharmaceutically acceptable salt,hydrate, or crystalline form thereof; and an anti-diabetic agent whichis a particular DPP-IV inhibitor, or a pharmaceutically acceptable salt,hydrate, or crystalline form thereof; as a combined preparation forsimultaneous, separate or sequential use in diabetes.

The present invention further relates to a drug product containing ananti-obesity agent which is a particular cannabinoid CB₁ receptorantagonist/inverse agonist, or a pharmaceutically acceptable salt,hydrate, or crystalline form thereof; and an anti-diabetic agent whichis a particular DPP-IV inhibitor, or a pharmaceutically acceptable salt,hydrate, or crystalline form thereof; as a combined preparation forsimultaneous, separate or sequential use in a diabetes-related disorder.

The present invention further relates to a drug product containing ananti-obesity agent which is a particular cannabinoid CB₁ receptorantagonist/inverse agonist, or a pharmaceutically acceptable salt,hydrate, or crystalline form thereof; and an anti-diabetic agent whichis a particular DPP-IV inhibitor, or a pharmaceutically acceptable salt,hydrate, or crystalline form thereof; as a combined preparation forsimultaneous, separate or sequential use in obesity.

The present invention further relates to a drug product containing ananti-obesity agent which is a particular cannabinoid CB₁ receptorantagonist/inverse agonist, or a pharmaceutically acceptable salt,hydrate, or crystalline form thereof; and an anti-diabetic agent whichis a particular DPP-IV inhibitor, or a pharmaceutically acceptable salt,hydrate, or crystalline form thereof; as a combined preparation forsimultaneous, separate or sequential use in an obesity-related disorder.

The present invention further relates to a drug product containing ananti-obesity agent which is a particular cannabinoid CB₁ receptorantagonist/inverse agonist, or a pharmaceutically acceptable salt,hydrate, or crystalline form thereof; and an anti-diabetic agent whichis a particular DPP-IV inhibitor, or a pharmaceutically acceptable salt,hydrate, or crystalline form thereof; as a combined preparation forsimultaneous, separate or sequential use in Metabolic Syndrome.

The present invention further relates to a drug product containing ananti-obesity agent which is a particular cannabinoid CB₁ receptorantagonist/inverse agonist, or a pharmaceutically acceptable salt,hydrate, or crystalline form thereof; and an anti-diabetic agent whichis a particular DPP-IV inhibitor, or a pharmaceutically acceptable salt,hydrate, or crystalline form thereof; as a combined preparation forsimultaneous, separate or sequential use in diabetes while mitigatingcardiac hypertrophy, particularly left ventricular hypertrophy.

The invention further provides pharmaceutical compositions comprising ananti-obesity agent which is a particular cannabinoid CB₁ receptorantagonist/inverse agonist, or a pharmaceutically acceptable salt,hydrate, or crystalline form thereof; and an anti-diabetic agent whichis a particular DPP-IV inhibitor, or a pharmaceutically acceptable salt,hydrate, or crystalline form thereof, as active ingredients.

The present invention further relates to the treatment or prevention ofdiabetes, diabetes associated with obesity, a diabetes-related disorder,obesity or an obesity-related disorder with a combination of ananti-obesity agent which is a particular cannabinoid CB₁ receptorantagonist/inverse agonist and an anti-diabetic agent which is aparticular DPP-IV inhibitor, which may be administered separately.Therefore the invention also relates to combining separatepharmaceutical compositions into a kit form. The kit, according to thisinvention, comprises two separate pharmaceutical compositions: a firstunit dosage form comprising a prophylactically or therapeuticallyeffective amount of a particular cannabinoid CB₁ receptorantagonist/inverse agonist, or a pharmaceutically acceptable salt,hydrate, or crystalline form thereof, and a pharmaceutically acceptablecarrier or diluent in a first unit dosage form, and a second unit dosageform comprising a prophylactically or therapeutically effective amountof a particular DPP-IV inhibitor, or a pharmaceutically acceptable salt,hydrate, or crystalline form thereof, and a pharmaceutically acceptablecarrier or diluent in a second unit dosage form.

The present invention also relates to a kit comprising at least one unitdosage of a prophylactically or therapeutically effective amount of aparticular cannabinoid CB₁ receptor antagonist/inverse agonist, or apharmaceutically acceptable salt, hydrate, or crystalline form thereof,and at least one unit dosage of a prophylactically or therapeuticallyeffective amount of a particular DPP-IV inhibitor, or a pharmaceuticallyacceptable salt, hydrate, or crystalline form thereof.

In one embodiment of the present invention, the kit further comprises acontainer. Such kits are especially suited for the delivery of solidoral forms such as tablets or capsules. Such a kit preferably includes anumber of unit dosages. Such kits can include a card having the dosagesoriented in the order of their intended use. An example of such a kit isa “blister pack”. Blister packs are well known in the packaging industryand are widely used for packaging pharmaceutical unit dosage forms. Ifdesired, a memory aid can be provided, for example in the form ofnumbers, letters, or other markings or with a calendar insert,designating the days or time in the treatment schedule in which thedosages can be administered.

Combination Therapy

The compositions of the present invention may be used in combinationwith other drugs that may also be useful in the treatment, prevention,or control of diabetes, diabetes associated with obesity,diabetes-related disorders, obesity, and obesity-related disorders forwhich compounds comprising the compositions are useful. Such other drugsmay be administered, by a route and in an amount commonly usedtherefore, contemporaneously or sequentially with a composition of thepresent invention. When a composition of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecomposition of the present invention is preferred. However, thecombination therapy also includes therapies in which the composition ofthe present invention and one or more other drugs are administered ondifferent overlapping schedules. It is also contemplated that when usedin combination with one or more other active ingredients, thecomposition of the present invention and the other active ingredientsmay be used in lower doses than when each is used singly. Accordingly,the pharmaceutical compositions of the present invention include thosethat contain one or more other active ingredients, in addition to acomposition of the present invention.

Examples of other active ingredients that may be administered incombination with a composition of the present invention, and eitheradministered separately or in the same pharmaceutical composition,include, but are not limited to:

(a) insulin sensitizers including (i) PPARα agonists, such as theglitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555,rosiglitazone, balaglitazone, and the like) and other PPAR ligands,including PPARα/γ dual agonists, such as KRP-297, muraglitazar,naveglitazar, tesaglitazar, and TAK-559; PPARα agonists, such asfenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate andbezafibrate); and selective PPARγ modulators (SPPARγM's), such asdisclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409,WO 2004/020408, and WO 2004/066963; (ii) biguanides, such as metforminand phenformin, and (iii) protein tyrosine phosphatase-1B (PTP-1B)inhibitors;

(b) insulin or insulin mimetics;

(c) sulfonylureas and other insulin secretagogues, such as tolbutamide,glyburide, glipizide, glimepiride, and meglitinides, such as nateglinideand repaglinide;

(d) α-glucosidase inhibitors (such as acarbose and miglitol);

(e) glucagon receptor antagonists, such as those disclosed in WO97/16442; WO 98/04528, WO 98/21957; WO 98/22108; WO 98/22109; WO99/01423, WO 00/39088, and WO 00/69810; WO 2004/050039; and WO2004/069158;

(f) GLP-1, GLP-1 analogues or mimetics, and GLP-1 receptor agonists,such as exendin-4 (exenatide), liraglutide (N,N-2211), CJC-1131,LY-307161, and those disclosed in WO 00/42026 and WO 00/59887;

(g) GIP and GIP mimetics, such as those disclosed in WO 00/58360, andGIP receptor agonists;

(h) PACAP, PACAP mimetics, and PACAP receptor agonists such as thosedisclosed in WO 01/23420;

(i) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin,atorvastatin, itavastatin, and rosuvastatin, and other statins), (ii)sequestrants (cholestyramine, colestipol, and dialkylaminoalkylderivatives of a cross-linked dextran), (iii) nicotinyl alcohol,nicotinic acid or a salt thereof, (iv) PPARα agonists, such asfenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate andbezafibrate), (v) PPARα/γ dual agonists, such as naveglitazar andmuraglitazar, (vi) inhibitors of cholesterol absorption, such asbeta-sitosterol and ezetimibe, (vii) acyl CoA:cholesterolacyltransferase inhibitors, such as avasimibe, and (viii) antioxidants,such as probucol;

(j) PPARδ agonists, such as those disclosed in WO 97/28149;

(k) antiobesity compounds, such as fenfluramine, dexfenfluramine,phentermine, sibutramine, orlistat, neuropeptide Y₁ or Y₅ antagonists,β₃ adrenergic receptor agonists, melanocortin-receptor agonists, inparticular melanocortin-4 receptor agonists, ghrelin antagonists,bombesin receptor agonists (such as bombesin receptor subtype-3agonists), and melanin-concentrating hormone (MCH) receptor antagonists;

(l) ileal bile acid transporter inhibitors;

(m) agents intended for use in inflammatory conditions such as aspirin,non-steroidal anti-inflammatory drugs NSAIDs), glucocorticoids,azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors;

(n) antihypertensive agents, such as ACE inhibitors (enalapril,lisinopril, captopril, quinapril, tandolapril), A-II receptor blockers(losartan, candesartan, irbesartan, valsartan, telmisartan, andeprosartan), beta blockers and calcium channel blockers;

(o) glucokinase activators (GKAs), such as those disclosed in WO03/015774; WO 04/076420; and WO 04/081001;

(p) inhibitors of 11β-hydroxysteroid dehydrogenase Type 1, such as thosedisclosed in U.S. Pat. No. 6,730,690; WO 03/104207; and WO 04/058741;

(q) inhibitors of cholesteryl ester transfer protein (CETP), such astorcetrapib; and

(r) inhibitors of fructose 1,6-bisphosphatase, such as those disclosedin U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and6,489,476.

The above combinations include combinations of a composition of thepresent invention not only with one other active compound, but also withtwo or more other active compounds. Non-limiting examples includecombinations of the compositions of the present invention with one, twoor more active compounds selected from anti-dyslipidemic agents andanti-hypertensive agents. Combinations of the compositions of thepresent invention with one, two, or more active compounds selected fromanti-dyslipidemic agents and anti-hypertensive agents will be useful totreat, control or prevent Metabolic Syndrome. Combinations of thecompositions of the present invention comprising a DPP-IV inhibitor anda cannabinoid CB₁ receptor antagonist/inverse agonist, in addition to ananti-dyslipidemic agent and/or an anti-hypertensive agent are moreefficacious in the treatment, control, or prevention of MetabolicSyndrome than treatment with any of these agents alone. In particular,compositions comprising a DPP-IV inhibitor and a cannabinoid CB₁receptor antagonist/inverse agonist, an anti-hypertensive agent and/oran anti-dyslipidemic agent will be useful to synergistically treat,control or prevent Metabolic Syndrome.

DEFINITIONS

The compounds in the compositions of the present invention includestereoisomers, such as optical isomers and diastereomers depending onthe mode of substitution. The compounds may contain one or more chiralcenters and occur as racemates, racemic mixtures and as individualdiastereomers, enantiomeric mixtures or single enantiomers, with allisomeric forms being included in the present invention. The presentinvention is meant to comprehend all such isomeric forms of thecompounds in the compositions of the present invention, and theirmixtures. Therefore, where a compound is chiral, the separateenantiomers, substantially free of the other, are included within thescope of the invention; further included are all mixtures of the twoenantiomers. Also included within the scope of the invention arecrystalline forms and hydrates, such as hydrates, of the compounds ofthe instant invention.

The independent syntheses of these stereoisomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the X-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

The present invention includes within its scope prodrugs of thecompounds in the compositions of this invention. In general, suchprodrugs will be functional derivatives of the compounds in thesecompositions which are readily convertible in vivo into the requiredcompound. Thus, in the methods of treatment of the present invention,the term “administering” shall encompass the treatment of diabetes,diabetes associated with obesity, diabetes-related disorders, obesity,and obesity-related disorders with the compounds specifically disclosedas elements of the composition or with compounds which may not bespecifically disclosed, but which convert to the specified compounds invivo after administration to the patient. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in “Design of Prodrugs,” ed. H. Bundgaard,Elsevier, 1985.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist as tautomers, whichhave different points of attachment of hydrogen accompanied by one ormore double bond shifts. For example, a ketone and its enol form areketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed with compounds of the present invention.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic or organic basesand inorganic or organic acids. Salts of basic compounds encompassedwithin the term “pharmaceutically acceptable salt” refer to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present inventioninclude, but are not limited to, the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, camsylate, carbonate, chloride, clavulanate, citrate, edetate,edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, hexylresorcinate, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammoniumsalt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate,subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodide and valerate. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof include, but are not limited to, salts derived frominorganic bases including aluminum, ammonium, calcium, copper, ferric,ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium,zinc, and the like. Particularly preferred are the ammonium, calcium,magnesium, potassium, and sodium salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, cyclic amines, and basicion-exchange resins, such as arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,isopropylamine, lysine, methylglucamine, morpholine, piperazine,piperidine, polyamine resins, procaine, purines, theobromine,triethylamine, trimethylamine, tripropylamine, tromethamine, and thelike.

The pharmaceutically acceptable salts of the composition of the instantinvention include the composition wherein one of the individualcomponents of the composition is in the form of a pharmaceuticallyacceptable salt, or the composition wherein all of the individualcomponents are in the form of pharmaceutically acceptable salts (whereinthe salts for each of the components can be the same or different), or apharmaceutically acceptable salt of the combined components (i.e., asalt of the composition).

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term, inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

Utilities:

The compositions of the present invention are useful for the treatmentor prevention of diabetes, and especially non-insulin dependent diabetesmellitus (NIDDM). The diabetes herein may be due to any cause, whethergenetic or environmental.

The compositions of the present invention are useful for the treatmentor prevention of diabetes associated with obesity. Diabetes associatedwith obesity may be associated with, caused by, or result from obesity.

The compositions of the present invention are useful for the treatmentor prevention of diabetes-related disorders. The diabetes-relateddisorders herein are associated with, caused by, or result fromdiabetes. Examples of diabetes-related disorders include hyperglycemia,impaired glucose tolerance, insulin resistance, obesity, lipiddisorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosisand its sequelae, vascular restenosis, irritable bowel syndrome,inflamatory bowel disease, including Crohn's disease and ulcerativecolitis, other inflammatory conditions, pancreatitis, abdominal obesity,neurodegenerative disease, retinopathy, neoplastic conditions, adiposecell tumors, adipose cell carcinomas, such as liposarcoma, prostatecancer and other cancers, including gastric, breast, bladder and coloncancers, angiogenesis, Alzheimer's disease, psoriasis, high bloodpressure, Metabolic Syndrome, ovarian hyperandrogenism (polycystic ovarysyndrome), and other disorders where insulin resistance is a component,such as sleep apnea. The compositions of the present invention areparticularly useful for the treatment, control or prevention ofhyperglycemia, impaired glucose tolerance, obesity, dyslipidemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDLlevels, atherosclerosis, and Metabolic Syndrome.

The compositions of the present invention are also useful for thetreatment or prevention of Metabolic Syndrome. The compositions of thepresent invention further comprising an anti-hypertensive agent and/oran anti-dyslipidemic agent are useful for the treatment or prevention ofMetabolic Syndrome.

The compositions of the present invention are useful for the treatmentor prevention of diabetes.

The compositions of the present invention are useful for the treatment,control, or prevention of obesity. The obesity herein may be due to anycause, whether genetic or environmental. The compositions comprised of aDPP-IV inhibitor and a cannabinoid CB₁ receptor antagonist/inverseagonist are also useful to treat and/or prevent the weight gainassociated with treatment with certain anti-diabetic agents, such asPPAR-γ agonists.

The compositions of the present invention are useful for the treatment,control, or prevention of obesity-related disorders. The obesity-relateddisorders herein are associated with, caused by, or result from obesity.Examples of obesity-related disorders include obesity, diabetes,overeating, binge eating, and bulimia, hypertension, elevated plasmainsulin concentrations and insulin resistance, dyslipidemia,hyperlipidemia, endometrial, breast, prostate, kidney and colon cancer,osteoarthritis, obstructive sleep apnea, gallstones, heart disease,abnormal heart rhythms and arrythmias, myocardial infarction, congestiveheart failure, coronary heart disease, sudden death, stroke, polycysticovarian syndrome, craniopharyngioma, Prader-Willi Syndrome, Frohlich'ssyndrome, GH-deficient subjects, normal variant short stature, Turner'ssyndrome, and other pathological conditions showing reduced metabolicactivity or a decrease in resting energy expenditure as a percentage oftotal fat-free mass, e.g, children with acute lymphoblastic leukemia.Further examples of obesity-related disorders are Metabolic Syndrome,insulin resistance syndrome, reproductive hormone abnormalities, sexualand reproductive dysfunction, such as impaired fertility, infertility,hypogonadism in males and hirsutism in females, fetal defects associatedwith maternal obesity, gastrointestinal motility disorders, such asobesity-related gastro-esophageal reflux, respiratory disorders, such asobesity-hypoventilation syndrome (Pickwickian syndrome), breathlessness,cardiovascular disorders, inflammation, such as systemic inflammation ofthe vasculature, arteriosclerosis, hypercholesterolemia, lower backpain, gallbladder disease, hyperuricemia, gout, and kidney cancer, andincreased anesthetic risk. The compositions of the present invention arealso useful to treat Alzheimer's disease and smoking.

The term “diabetes,” as used herein, includes both insulin-dependentdiabetes mellitus (i.e., IDDM, also known as Type 1 diabetes) andnon-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as Type2 diabetes). Type 1 diabetes, or insulin-dependent diabetes, is theresult of an absolute deficiency of insulin, the hormone which regulatesglucose utilization. Type 2 diabetes, or insulin-independent diabetes(i.e., non-insulin-dependent diabetes mellitus), often occurs in theface of normal, or even elevated levels of insulin and appears to be theresult of the inability of tissues to respond appropriately to insulin.The development of Type 2 diabetes is related to obesity; most of theType 2 diabetics are also obese. The compositions of the presentinvention are useful for treating both Type 1 and Type 2 diabetes. Thecompositions of the present invention are especially effective intreating diabetes associated with obesity. The term “diabetes associatedwith obesity” refers to diabetes caused by obesity or resulting fromobesity. The compositions are especially effective for treating Type 2diabetes. The compositions of the present invention are also useful fortreating and/or preventing gestational diabetes mellitus.

Diabetes is characterized by a fasting plasma glucose level of greaterthan or equal to 126 mg/dl. A diabetic subject has a fasting plasmaglucose level of greater than or equal to 126 mg/dl. Prediabetes ischaracterized by an impaired fasting plasma glucose (FPG) level ofgreater than or equal to 110 mg/dl and less than 126 mg/dl; or impairedglucose tolerance; or insulin resistance. A prediabetic subject is asubject with impaired fasting glucose (a fasting plasma glucose (FPG)level of greater than or equal to 110 mg/dl and less than 126 mg/dl); orimpaired glucose tolerance (a 2 hour plasma glucose level of >140 mg/dland <200 mg/dl); or insulin resistance, resulting in an increased riskof developing diabetes.

Treatment of diabetes mellitus refers to the administration of acombination of the present invention to treat a diabetic subject. Oneoutcome of treatment may be decreasing the glucose level in a subjectwith elevated glucose levels. Another outcome of treatment may bedecreasing insulin levels in a subject with elevated insulin levels.Another outcome of treatment may be decreasing plasma triglycerides in asubject with elevated plasma triglycerides. Another outcome of treatmentis decreasing LDL cholesterol in a subject with high LDL cholesterollevels. Another outcome of treatment may be increasing HDL cholesterolin a subject with low HDL cholesterol levels. Another outcome oftreatment is increasing insulin sensitivity. Another outcome oftreatment may be enhancing glucose tolerance in a subject with glucoseintolerance. Yet another outcome of treatment may be decreasing insulinresistance in a subject with increased insulin resistance or elevatedlevels of insulin. Prevention of diabetes mellitus, in particulardiabetes associated with obesity, refers to the administration of acompound or combination of the present invention to prevent the onset ofdiabetes in a subject in need thereof. A subject in need of preventingdiabetes is a prediabetic subject that is overweight or obese.

The term “hypertension” as used herein includes essential, or primary,hypertension wherein the cause is not known or where hypertension is dueto greater than one cause, such as changes in both the heart and bloodvessels; and secondary hypertension wherein the cause is known. Causesof secondary hypertension include, but are not limited to obesity;kidney disease; hormonal disorders; use of certain drugs, such as oralcontraceptives, corticosteroids, cyclosporin, and the like. The term“hypertension” encompasses high blood pressure, in which both thesystolic and diastolic pressure levels are elevated (>140 mmHg/>90mmHg), and isolated systolic hypertension, in which only the systolicpressure is elevated to greater than or equal to 140 mm Hg, while thediastolic pressure is less than 90 mm Hg. Normal blood pressure may bedefined as below 120 mm Hg (systolic pressure) over 80 mm Hg (diastolicpressure). A hypertensive subject is a subject with hypertension. Apre-hypertensive subject is a subject with a blood pressure that isbetween 120 mmHg over 80 mmHg and 139 mmHg over 89 mmHg. One outcome oftreatment is decreasing blood pressure in a subject with high bloodpressure. Treatment of hypertension refers to the administration of thecombinations of the present invention to treat hypertension in ahypertensive subject. Prevention of hypertension refers to theadministration of the combinations of the present invention to apre-hypertensive subject to prevent the onset of hypertension or ahypertension related disorder.

Dyslipidemias or disorders of lipid metabolism, include variousconditions characterized by abnormal concentrations of one or morelipids (i.e. cholesterol and triglycerides), and/or apolipoproteins(i.e., apolipoproteins A, B, C and E), and/or lipoproteins (i.e., themacromolecular complexes formed by the lipid and the apolipoprotein thatallow lipids to circulate in blood, such as LDL, VLDL and IDL).Hyperlipidemia is associated with abnormally high levels of lipids, LDLand VLDL cholesterol, and/or triglycerides. Treatment of dyslipidemiarefers to the administration of the combinations of the presentinvention to a dyslipidemic subject. Prevention of dyslipidemia refersto the administration of the combinations of the present invention to apre-dyslipidemic subject. A pre-dyslipidemic subject is a subject withhigher than normal lipid levels that is not yet dyslipidernic.

The term “Metabolic Syndrome” is defined in the Third Report of theNational Cholesterol Education Program Expert Panel on Detection,Evaluation and Treatment of High Blood Cholesterol in Adults (ATP-III).E. S. Ford et al., JAMA, vol. 287 (3), Jan. 16, 2002, pp 356-359.Briefly, a person is defined as having Metabolic Syndrome if the personhas three or more of the following disorders: abdominal obesity,hypertriglyceridemia, low HDL cholesterol, high blood pressure, and highfasting plasma glucose. The criteria for these are defined in ATP-III.Treatment of Metabolic Syndrome refers to the administration of thecombinations of the present invention to a subject with MetabolicSyndrome. Prevention of Metabolic Syndrome refers to the administrationof the combinations of the present invention to a subject with two ofthe disorders that define Metabolic Syndrome. A subject with two of thedisorders that define Metabolic Syndrome is a subject that has developedtwo of the disorders that define Metabolic Syndrome, but has not yetdeveloped three or more of the disorders that define Metabolic Syndrome.

Left ventricular hypertrophy (LVH) is identified based on leftventricular mass index (LVMI) and relative wall thickness (RWT). Leftventricular mass index is defined as left ventricular mass in gramsdivided by body surface area in meters². Relative wall thickness isdefined as 2× posterior wall thickness/left ventricular end diastolicdiameter. Normal LVMI values are typically 85 and normal RWTapproximately 0.36. A male subject with LVH has a LVMI greater than 131g/m²; a female subject with LVH has a LVMI greater than 100 g/m². Asubject with an elevated LVMI value is a male subject with a LVMIbetween 85 g/m² and 131 g/m², or a female subject with a LVMI between 85g/m² and 100 g/m². Treatment of cardiac hypertrophy, or left ventricularhypertrophy, refers to the administration of the combinations of thepresent invention to a subject with cardiac hypertrophy or leftventricular hypertrophy. Prevention of cardiac hypertrophy, or leftventricular hypertrophy, refers to the administration of thecombinations of the present invention to decrease or maintain the LVMIin a subject with an elevated LVMI value or to prevent the increase ofLVMI in a subject with a normal LVMI value.

One outcome of treatment of cardiac hypertrophy or left ventricularhypertrophy may be a decrease in ventricular mass. Another outcome oftreatment of cardiac hypertrophy or left ventricular hypertrophy may bea decrease in the rate of increase of ventricular mass. Another outcomeof treatment of cardiac hypertrophy or left ventricular hypertrophy maybe a decrease in ventricular wall thickness. Another outcome oftreatment of cardiac hypertrophy of left ventricular hypertrophy may bethe decrease in the rate of increase in ventricular wall thickness. Oneoutcome of treatment of diabetes while mitigating cardiac hypertrophy,or left ventricular hypertrophy, may be a decrease in ventricular mass.Another outcome of treatment of diabetes while mitigating cardiachypertrophy or left ventricular hypertrophy may be a decrease in therate of increase of ventricular mass. Another outcome of treatment ofdiabetes while mitigating cardiac hypertrophy or left ventricularhypertrophy may be a decrease in ventricular wall thickness. Anotheroutcome of treatment of diabetes while mitigating cardiac hypertrophy ofleft ventricular hypertrophy may be the decrease in the rate of increasein ventricular wall thickness.

The term “obesity” as used herein is a condition in which there is anexcess of body fat. The operational definition of obesity is based onthe Body Mass Index (BMI), which is calculated as body weight per heightin meters squared (kg/m²). “Obesity” refers to a condition whereby anotherwise healthy subject has a Body Mass Index (BMI) greater than orequal to 30 kg/m², or a condition whereby a subject with at least oneco-morbidity has a BMI greater than or equal to 27 kg/m². An “obesesubject” is an otherwise healthy subject with a Body Mass Index (BMI)greater than or equal to 30 kg/m² or a subject with at least oneco-morbidity with a BMI greater than or equal to 27 kg/m². A “subject atrisk of obesity” is an otherwise healthy subject with a BMI of 25 kg/m²to less than 30 kg/m² or a subject with at least one co-morbidity with aBMI of 25 kg/m² to less than 27 kg/m².

The increased risks associated with obesity occur at a lower Body MassIndex (BMI) in Asians. In Asian countries, including Japan, “obesity”refers to a condition whereby a subject with at least oneobesity-induced or obesity-related co-morbidity, that requires weightreduction or that would be improved by weight reduction, has a BMIgreater than or equal to 25 kg/m². In Asian countries, including Japan,an “obese subject” refers to a subject with at least one obesity-inducedor obesity-related co-morbidity that requires weight reduction or thatwould be improved by weight reduction, with a BMI greater than or equalto 25 kg/m². In Asia-Pacific, a “subject at risk of obesity” is asubject with a BMI of greater than 23 kg/m² to less than 25 kg/m².

As used herein, the term “obesity” is meant to encompass all of theabove definitions of obesity.

Obesity-induced or obesity-related co-morbidities include, but are notlimited to, diabetes, non-insulin dependent diabetes mellitus (Type 2),diabetes associated with obesity, impaired glucose tolerance, impairedfasting glucose, insulin resistance syndrome, dyslipidemia,hypertension, hypertension associated with obesity, hyperuricacidemia,gout, coronary artery disease, myocardial infarction, angina pectoris,sleep apnea syndrome, Pickwickian syndrome, fatty liver; cerebralinfarction, cerebral thrombosis, transient ischemic attack, orthopedicdisorders, arthritis deformans, lumbodynia, emmeniopathy, andinfertility, lower back pain, and increased anesthetic risk. Inparticular, co-morbidities include: hypertension, hyperlipidemia,dyslipidemia, glucose intolerance, cardiovascular disease, sleep apnea,diabetes mellitus, and other obesity-related conditions.

Treatment of obesity and obesity-related disorders refers to theadministration of the combinations of the present invention to reduce ormaintain the body weight of an obese subject. One outcome of treatmentmay be reducing the body weight of an obese subject relative to thatsubject's body weight immediately before the administration of thecompounds or combinations of the present invention. Another outcome oftreatment may be preventing body weight regain of body weight previouslylost as a result of diet, exercise, or pharmacotherapy and preventingweight gain from cessation of smoking. Another outcome of treatment maybe decreasing the occurrence of and/or the severity of obesity-relateddiseases. Yet another outcome of treatment may be decreasing the risk ofdeveloping diabetes in an overweight or obese subject. The treatment maysuitably result in a reduction in food or calorie intake by the subject,including a reduction in total food intake, or a reduction of intake ofspecific components of the diet such as carbohydrates or fats; and/orthe inhibition of nutrient absorption; and/or the inhibition of thereduction of metabolic rate; and in weight reduction in patients in needthereof. The treatment may also result in an alteration of metabolicrate, such as an increase in metabolic rate, rather than or in additionto an inhibition of the reduction of metabolic rate; and/or inminimization of the metabolic resistance that normally results fromweight loss.

Prevention of obesity and obesity-related disorders refers to theadministration of the combinations of the present invention to reduce ormaintain the body weight of a subject at risk of obesity. One outcome ofprevention may be reducing the body weight of a subject at risk ofobesity relative to that subject's body weight immediately before theadministration of the compounds or combinations of the presentinvention. Another outcome of prevention may be preventing body weightregain of body weight previously lost as a result of diet, exercise, orpharmacotherapy. Another outcome of prevention may be preventing obesityfrom occurring if the treatment is administered prior to the onset ofobesity in a subject at risk of obesity. Another outcome of preventionmay be decreasing the occurrence and/or severity of obesity-relateddisorders if the treatment is administered prior to the onset of obesityin a subject at risk of obesity. Moreover, if treatment is commenced inalready obese subjects, such treatment may prevent the occurrence,progression or severity of obesity-related disorders, such as, but notlimited to, arteriosclerosis, Type 2 diabetes, polycystic ovary disease,cardiovascular diseases, osteoarthritis, dermatological disorders,hypertension, insulin resistance, hypercholesterolemia,hypertriglyceridemia, and cholelithiasis.

In particular, the compositions of the present invention are useful tothe treatment of atherosclerosis. The term “atherosclerosis” as usedherein encompasses vascular diseases and conditions that are recognizedand understood by physicians practicing in the relevant fields ofmedicine. Atherosclerotic cardiovascular disease, coronary heart disease(also known as coronary artery disease or ischemic heart disease),cerebrovascular disease and peripheral vessel disease are all clinicalmanifestations of atherosclerosis and are therefore encompassed by theterms “atherosclerosis” and “atherosclerotic disease.” The compositioncomprised of a therapeutically or prophylactically effective amount of aDPP-IV inhibitor in combination with a therapeutically orprophylactically effective amount of a cannabinoid CB₁ receptorantagonist/inverse agonist may be administered to prevent or reduce therisk of occurrence, or recurrence where the potential exists, of acoronary heart disease event, a cerebrovascular event, or intermittentclaudication. Coronary heart disease events are intended to include CHDdeath, myocardial infarction (i.e., a heart attack), and coronaryrevascularization procedures. Cerebrovascular events are intended toinclude ischemic or hemorrhagic stroke (also known as cerebrovascularaccidents) and transient ischemic attacks. Intermittent claudication isa clinical manifestation of peripheral vessel disease. The term“atherosclerotic disease event” as used herein is intended to encompasscoronary heart disease events, cerebrovascular events, and intermittentclaudication. It is intended that persons who have previouslyexperienced one or more non-fatal atherosclerotic disease events arethose for whom the potential for recurrence of such an event exists.

The terms “administration of” and or “administering a” compositionshould be understood to mean providing a composition of the invention toa subject in need of treatment. The instant pharmaceutical compositionsinclude administration of a single pharmaceutical dosage formulationwhich contains a DPP-IV inhibitor and a cannabinoid CB₁ receptorantagonist/inverse agonist, as well as administration of each activeagent in its own separate pharmaceutical dosage formulation. Whereseparate dosage formulations are used, the individual components of thecomposition can be administered at essentially the same time, i.e.,concurrently, or at separately staggered times, i.e. sequentially priorto or subsequent to the administration of the other component of thecomposition. The instant pharmaceutical composition is therefore to beunderstood to include all such regimes of simultaneous or alternatingtreatment, and the terms “administration” and “administering” are to beinterpreted accordingly. Administration in these various ways aresuitable for the present compositions as long as the beneficialpharmaceutical effect of the combination of the anti-obesity agent andthe anti-diabetic agent is realized by the patient at substantially thesame time. Such beneficial effect is preferably achieved when the targetblood level concentrations of each active drug are maintained atsubstantially the same time. It is preferred that the combination of theDPP-IV inhibitor and the cannabinoid CB₁ receptor antagonist/inverseagonist be co-administered concurrently on a once-a-day dosing schedule;however, varying dosing schedules, such as the anti-obesity agent once aday and the anti-diabetic agent once, twice or more times per day, isalso encompassed herein. A single oral dosage formulation comprised ofboth agents in the combination is preferred. A single dosage formulationwill provide convenience for the patient, which is an importantconsideration especially for patients with diabetes, Metabolic Syndrome,or obese patients who may be in need of multiple medications.

The term “subject”, as used herein refers to a mammal, preferably ahuman, who has been the object of treatment, observation or experiment.In one embodiment the term “mammal” is a “human” said human being eithermale or female. The instant combinations are also useful for treating orpreventing obesity and obesity-related disorders in cats and dogs. Assuch, the term “mammal” includes companion animals such as cats anddogs.

The term “subject in need thereof” refers to a subject who is in need oftreatment or prophylaxis as determined by a researcher, veterinarian,medical doctor or other clinician. In one embodiment, a subject in needthereof is a mammal. In another embodiment, a subject in need thereof isan obese subject. In another embodiment, a subject in need thereof is anobese subject with diabetes. In another embodiment, a subject in needthereof is an obese subject at risk of developing diabetes. In anotherembodiment, a subject in need thereof is a diabetic subject. In anotherembodiment, a subject in need thereof is an obese diabetic subject. Inanother embodiment, a subject in need thereof is a diabetic subject atrisk of developing obesity. In another embodiment, a subject in needthereof is an obese subject with Metabolic Syndrome. In anotherembodiment, a subject in need thereof is an obese subject at risk ofdeveloping Metabolic Syndrome. In another embodiment, a subject in needthereof is a diabetic subject with Metabolic Syndrome. In anotherembodiment, a subject in need thereof is a diabetic subject at risk ofdeveloping Metabolic Syndrome. In another embodiment, a subject in needthereof is an obese diabetic subject with Metabolic Syndrome. In anotherembodiment, a subject in need thereof is an obese subject at risk ofdeveloping Metabolic Syndrome. In another embodiment, a subject in needthereof is a diabetic subject at risk of developing Metabolic Syndrome.In another embodiment, a subject in need thereof is an obese diabeticsubject at risk of developing Metabolic Syndrome.

In another embodiment, a subject in need thereof is an obese subjectwith cardiac hypertrophy, or left ventricular hypertrophy. In anotherembodiment, a subject in need thereof is a diabetic subject with cardiachypertrophy, or left ventricular hypertrophy. In another embodiment, asubject in need thereof is an obese diabetic subject with cardiachypertrophy, or left ventricular hypertrophy. In another embodiment, asubject in need thereof is an obese subject at risk of developingcardiac hypertrophy, or left ventricular hypertrophy. In anotherembodiment, a subject in need thereof is a diabetic subject at risk ofdeveloping cardiac hypertrophy, or left ventricular hypertrophy. Inanother embodiment, a subject in need thereof is an obese diabeticsubject at risk of developing cardiac hypertrophy, or left ventricularhypertrophy. In another embodiment, a subject in need thereof is anobese diabetic subject with cardiac hypertrophy, or left ventricularhypertrophy, undergoing PPARγ agonist treatment. In another embodiment,a subject in need thereof is an obese diabetic subject undergoing PPARγagonist treatment and at risk of developing cardiac hypertrophy, or leftventricular hypertrophy.

The administration of the composition of the present invention in orderto practice the present methods of therapy is carried out byadministering a therapeutically or prophylactically effective amount ofthe compounds in the composition to a subject in need of such treatmentor prophylaxis. The need for a prophylactic administration according tothe methods of the present invention is determined via the use of wellknown risk factors. The effective amount of an individual compound isdetermined, in the final analysis, by the physician in charge of thecase, but depends on factors such as the exact disease to be treated,the severity of the disease and other diseases or conditions from whichthe patient suffers, the chosen route of administration, other drugs andtreatments which the patient may concomitantly require, and otherfactors in the physician's judgment.

The term “therapeutically effective amount” as used herein means theamount of the active compounds in the composition that will elicit thebiological or medical response in a tissue, system, subject, or humanthat is being sought by the researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisorder being treated. The novel methods of treatment of this inventionare for disorders known to those skilled in the art.

The term “prophylactically effective amount” as used herein means theamount of the active compounds in the composition that will elicit thebiological or medical response in a tissue, system, subject, or humanthat is being sought by the researcher, veterinarian, medical doctor orother clinician, to prevent the onset of diabetes, diabetes associatedwith obesity, a diabetes associated disorder, obesity or anobesity-related disorder in a subject at risk of developing thedisorder.

The magnitude of prophylactic or therapeutic dose of the activeingredients of the composition may vary with the nature of the severityof the condition to be treated and with the particular compound in thecomposition and its route of administration. It will also vary accordingto the age, weight and response of the individual patient. In general,the daily dose range of each compound in the combination lies within therange of from about 0.0001 mg/kg to about 100 mg/kg, preferably fromabout 0.001 mg/kg to about 50 mg/kg body weight of a subject in singleor divided doses. On the other hand, it may be necessary to use dosagesoutside these limits in some cases.

In the case where an oral composition is employed, a suitable dosagerange is, e.g. from about 0.001 mg/kg to about 100 mg/kg of eachcompound in the composition per day, preferably from about 0.01 mg toabout 2000 mg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing from 0.01 mg to1,000 mg, e.g. 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25,30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 750, 850, 1,000and 2,000 milligrams of each active ingredient for the symptomaticadjustment of the dosage to the subject to be treated. This dosageregimen may be adjusted to provide the optimal therapeutic response.

The anti-diabetic DPP-IV inhibitors in the combinations of the presentinvention are administered at a daily dosage of from about 0.1 mg toabout 100 mg per kilogram of animal body weight, preferably given as asingle daily dose or in divided doses two to six times a day, or insustained release form. For most large mammals, the total daily dosageis from about 1.0 mg to about 1000 mg, preferably from about 10 mg toabout 200 mg. In the case of a 70 kg adult human, the total daily dosewill generally be from about 7 mg to about 350 mg. This dosage regimenmay be adjusted to provide the optimal therapeutic response.

In one embodiment the substituted amide cannabinoid CB₁ receptorantagonist/inverse agonists disclosed in international patentpublication WO 2003/077847 are administered at a total daily dosage offrom about 1.0 mg to about 1000 mg, preferably from about 1 mg to about50 mg. In the case of a 70 kg adult human, the total daily dose willgenerally be from about 1 mg to about 35 mg. This dosage regimen may beadjusted to provide the optimal therapeutic response.

The effective dosage of each of the active ingredients employed in thecomposition may vary depending on the particular compound employed, themode of administration, the condition being treated and the severity ofthe condition being treated. Thus, the dosage regimen utilizing thecompositions of the present invention is selected in accordance with avariety of factors including type, species, age, general health, bodyweight, diet, sex and medical condition of the subject; the severity ofthe condition to be treated; the renal and hepatic function of thepatient; the drug combination; and the particular compounds employed andtheir routes of administration. A physician, clinician or veterinarianof ordinary skill can readily determine and prescribe the effectiveamount of the drug required to prevent, counter or arrest the progressof the condition.

The weight ratio of the agents in the combinations of the presentinvention may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used.

Another aspect of the present invention provides pharmaceuticalcompositions comprising a pharmaceutical carrier and a therapeuticallyor prophylactically effective amount of each compound in the compositionof the present invention. The term “composition”, as in pharmaceuticalcomposition, is intended to encompass a product comprising the activeingredient(s), and the inert ingredient(s), such as pharmaceuticallyacceptable excipients, that make up the carrier, as well as any productwhich results, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing an anti-obesity agent and an anti-diabeticagent, and pharmaceutically acceptable excipients.

Any suitable route of administration may be employed for providing asubject, especially a human, with an effective dosage of a compositionof the present invention. For example, oral, rectal, topical,parenteral, ocular, pulmonary, nasal, and the like may be employed.Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, creams, ointments, aerosols, and the like.

The pharmaceutical compositions of the present invention comprise acombination of a DPP-IV inhibitor and a cannabinoid CB₁ receptorantagonist/inverse agonist, as active ingredients, or a pharmaceuticallyacceptable salt or ester thereof, and may also contain apharmaceutically acceptable carrier and optionally other therapeuticingredients. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof. Inparticular, the term “pharmaceutically acceptable salts” refers to saltsprepared from pharmaceutically acceptable non-toxic bases or acidsincluding inorganic bases or acids and organic bases or acids.

The compositions include compounds suitable for oral, rectal, topical,parenteral (including subcutaneous, intramuscular, and intravenous),ocular (ophthalmic), pulmonary (aerosol inhalation), or nasaladministration, although the most suitable route in any given case willdepend on the nature and severity of the conditions being treated and onthe nature of the active ingredient. These compositions may beconveniently presented in unit dosage form and prepared by any of themethods well-known in the art of pharmacy.

For administration by inhalation, the compositions of the presentinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or nebulizers. The compositions mayalso be delivered as powders which may be formulated and the powdercomposition may be inhaled with the aid of an insufflation powderinhaler device. The preferred delivery systems for inhalation aremetered dose inhalation (MDI) aerosol, which may be formulated as asuspension or solution of the instant composition in suitablepropellants, such as fluorocarbons or hydrocarbons and dry powderinhalation (DPI) aerosol, which may be formulated as a dry powder of thecomposition with or without additional excipients.

Suitable topical formulations of the compositions of the presentinvention include transdermal devices, aerosols, creams, solutions,ointments, gels, lotions, dusting powders, and the like. The topicalpharmaceutical compositions containing the compositions of the presentinvention ordinarily include about 0.005% to 5% by weight of the activecompounds in admixture with a pharmaceutically acceptable vehicle.Transdermal skin patches useful for administering the compositions ofthe present invention include those well known to those of ordinaryskill in that art. To be administered in the form of a transdermaldelivery system, the dosage administration will, of course be continuousrather than intermittent throughout the dosage regimen.

The compositions of the present invention can also be administered inthe form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, sterylamine or phosphatidylcholines.

Compositions of the present invention may also be delivered by the useof monoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds in these compositions may also becoupled with soluble polymers as targetable drug carriers. Such polymerscan include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropyl-methacrylamide phenol,polyhydroxyethylasparamidepheon, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compositions ofthe present invention may be coupled to a class of biodegradablepolymers useful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compositions of the present invention may also be delivered as asuppository employing bases such as cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

In practical use, each compound in the compositions of the presentinvention can be combined as the active ingredients in intimateadmixture with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending on the form of preparation desired foradministration, e.g., oral or parenteral (including intravenous). Inpreparing the compositions for oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents and the like in the case of oral liquid preparations, such as,for example, suspensions, elixirs and solutions; or carriers such asstarches, sugars, microcrystalline cellulose, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like in thecase of oral solid preparations such as, for example, powders, capsules,pellet, powder and tablets, with the solid oral preparations beingpreferred over the liquid preparations. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit form in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compositionmay also be administered by controlled release means and/or deliverydevices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; 3,630,200; and 4,008,719.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules(including timed release and sustained release formulations), pills,cachets, powders, granules or tablets each containing a predeterminedamount of the active ingredients, as a powder or granules or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion or a water-in-oil liquid emulsion, includingelixirs, tinctures, solutions, suspensions, syrups and emulsions. Suchcompositions may be prepared by any of the methods of pharmacy but allmethods include the step of bringing into association the activeingredient with the carrier which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation. For example, a tablet may beprepared by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine, the active ingredient in a free-flowing form suchas powder or granules, optionally mixed with a binder, lubricant, inertdiluent, surface active or dispersing agent. Molded tablets may be madeby molding in a suitable machine, a mixture of the powdered compoundmoistened with an inert liquid diluent.

For example, for oral administration in the form of a tablet, capsule,pellet, or powder, the active ingredient can be combined with an oral,non-toxic, pharmaceutically acceptable inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,mannitol, sorbitol, croscarmellose sodium and the like; for oraladministration in liquid form, e.g., elixirs, syrups, slurries,emulsions, suspensions, solutions, and effervescent compositions, theoral drug components can be combined with any oral, non-toxic,pharmaceutically acceptable inert carrier such as ethanol, glycerol,water, oils and the like. Moreover, when desired or necessary, suitablebinders, lubricants, disintegrating agents, buffers, coatings, andcoloring agents can also be incorporated. Suitable binders can includestarch, gelatin, natural sugars such a glucose, anhydrous lactose,free-flow lactose, beta-lactose, and corn sweeteners, natural andsynthetic gums, such as acacia, guar, tragacanth or sodium alginate,carboxymethyl cellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Various other materials may be present ascoatings or to modify the physical form of the dosage unit. Forinstance, tablets may be coated with shellac, sugar or both. A syrup orelixir may contain, in addition to the active ingredient, sucrose as asweetening agent, methyl and propylparabens as preservatives, a dye anda flavoring such as cherry or orange flavor. When a dosage unit form isa capsule, it may contain, in addition to materials of the above type, aliquid carrier such as a fatty oil.

Desirably, each tablet contains from 0.01 to 1,000 mg, particularly0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75,100, 125, 150, 175, 200, 225, 250, 500, 750, 850 and 1,000 milligrams ofeach active ingredient in the composition of the present invention forthe symptomatic adjustment of the dosage to the subject to be treated;and each cachet or capsule contains from about 0.01 to 1,000 mg,particularly 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30,40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 750, 850 and 1,000milligrams of each active ingredient in the composition of the presentinvention for the symptomatic adjustment of the dosage to the subject tobe treated.

Exemplifying the invention is a pharmaceutical composition comprising aDPP-IV inhibitor and a CB₁ cannabinoid receptor antagonist/inverseagonist described above and a pharmaceutically acceptable carrier.

Also exemplifying the invention is a pharmaceutical composition made bycombining any of the DPP-IV inhibitors and cannabinoid CB₁ receptorantagonist/inverse agonists described above and a pharmaceuticallyacceptable carrier. An illustration of the invention is a process formaking a pharmaceutical composition comprising combining any of theanti-obesity agents and anti-diabetic agents described above and apharmaceutically acceptable carrier.

The dose may be administered in a single daily dose or the total dailydosage may be administered in divided doses of two to six times daily.Furthermore, based on the properties of the individual compound selectedfor administration, the dose may be administered less frequently, e.g.,weekly, twice weekly, monthly, etc. The unit dosage will, of course, becorrespondingly larger for the less frequent administration.

When administered via intranasal routes, transdermal routes, by rectalor vaginal suppositories, or through a continual intravenous solution,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

The following is an examples of a representative pharmaceutical dosageform for the compositions of the present invention:

Tablet 150 mg/tablet Compound of formula III 10 mg MK-0431* 64.25 mgMicrocrystalline Cellulose 53.19 mg Hydroxypropylcellulose 9 mgCroscarmellose Sodium 9 mg Magnesium Stearate 4.5 mg Butylatedhydroxyanisole (BHA) 0.06 mg 64.25 mg of the dihydrogenphosphate salt isequivalent to 50 mg of the free base

Method of Manufacture:

The steps involved in the direct compression method comprise:

-   (1) blending Compound of formula III, MK-0431, and croscarmellose    sodium in a V-blender or other suitable blender for a period of    about 5 to 30 min;-   (2) adding hydroxypropyl cellulose and microcrystalline cellulose to    improve compaction properties;-   (3) lubricating with magnesium stearate for about 1 to 15 min;-   (4) compressing the lubricated blend into a desired tablet image;    and, if desired,-   (5) film-coating.

An antioxidant, such as BHA or BHT, can be added by either layering itonto one of the excipients prior to blending with Compound of formulaIII and MK-0431 and the other excipients or by layering it onto Compoundof formula III and MK-0431 during the bulk drug synthesis process. Thetablets are optionally coated with 6.00 mg of a standard HPC/HPMC/TiO₂film-coat formula (Opadry I®) to provide a 156-mg coated tablet.

It will be understood that the scope of compositions of the compounds ofthis invention with other agents useful for treating or preventingobesity and obesity-related conditions includes in principle anycombination with any pharmaceutical composition useful for treatingobesity and obesity-related disorders.

In order to illustrate the invention, the following examples areincluded. These examples do not limit the invention. They are only meantto suggest a method of reducing the invention to practice. Those skilledin the art may find other methods of practicing the invention which arereadily apparent to them. However, those methods are also deemed to bewithin the scope of this invention.

The substituted amide cannabinoid CB₁ receptor antagonist/inverseagonists from international patent publication WO 2003/077847 (published24 Sep. 2003) were prepared following the synthetic methods disclosedtherein and exemplified by the synthesis ofN-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamideof structural formula III below:

Preparation of Intermediate2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoic acid (1)

Step 1: Ethyl2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoate

A mixture of 2-hydroxy-5-trifluoromethylpyridine (5.73 g, 39 mmol),ethyl 2-bromoisobutyrate (5.7 mL, 39 mmol) and cesium carbonate (25 g,77 mmol) in 50 mL acetonitrile was heated at 5° C. overnight. Thevolatile materials were removed by concentrating on a rotary evaporator,and the residue was partitioned between water (100 mL) and EtOAc (100mL). The organic layer was separated and the aqueous layer extractedwith EtOAc (2×100 mL). The combined organic extracts were dried overanhydrous sodium sulfate, filtered and concentrated to dryness, and theresidue was purified by flash column chromatography on silica gel elutedwith 5% EtOAc in hexane to give the title compound. ¹H NR (500 MHz,CD₃OD): δ 7.99 (d, 1H), 7.67 (dd, 1H), 6.68 (d, 1H), 4.13 (q, 2H), 1.64(s, 6H), 1.14 (t, 3H). LC-MS: m/e 244 (M+H)⁺ (3.41 min).

Step 2: 2-Methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoic acid(1)

A mixture of ethyl2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoate and sodiumhydroxide (0.85 g, 21 mmol) in 15 mL acetonitrile and 15 mL water washeated at 50° C. overnight. The volatile materials were removed byconcentrating on a rotary evaporator, and the residue was partitionedbetween 2 M hydrochloric acid (100 mL) and ether (100 mL). The organiclayer was separated and washed with water (2×50 mL), dried overanhydrous MgSO₄, filtered and concentrated to dryness to give the titlecompound. ¹H NMR (500 MHz, CD₃OD): δ 8.38 (br s, 1H), 7.93 (dd, 1H),7.13 (d, 1H), 1.70 (s, 6H). LC-MS: m/e 250 (M+H)⁺ (2.6 min).

Step A: Preparation of2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-propanamide (2)

In a 12 L 3-neck separatory funnel equipped with overhead stirrer,nitrogen inlet and thermocouple, a solution of2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoic acid (1) (772g) in MeCN (6.5 L) was prepared. Thionyl chloride (316 mL) was addedover 30 min. The resulting solution was stirred at room temperature for2 h. A separate 22 L 3-necked round bottom flask equipped with overheadstirrer, nitrogen inlet and thermocouple, was charged with 30% aqueousNH₄OH (5 L) and cooled to −20° C. The acid chloride solution from theseparatory funnel was added to the solution of NH₄OH at such a rate thatthe internal reaction temperature was kept at −15 to −20° C. over 2 h.Once the addition was complete, the resulting slurry was warmed to roomtemperature and stirred for an additional 1 h. The reaction mixture wastransferred to a 50-L extractor containing toluene (15 L) and water (15L), and the layers were separated. The organic layer was washed withsaturated aqueous NaHCO₃ (5 L), and then with water (5 L). The organiclayer was transferred to a 12-L four-neck round bottom flask, andconcentrated under vacuum at 50° C. to about 2 L volume. Near the end ofthe concentration, the solid began to precipitate, and the batch washeated to 78° C. to dissolve all of the solids. Heptane (5 L) was addedand the batch was allowed to slowly cool, affording a crystalline solid.The slurry was filtered, and the filter cake was washed with n-heptane(1 L). The resulting solid was dried under a stream of nitrogen toafford the title compound.

Step B: Preparation of 3-[1-(4-chlorobenzyl)-2-oxopropyl]benzonitrile(4)

Catalyst Preparation:

A 4-neck 12 L round bottom flask equipped with thermocouple, overheadstirrer, rubber septum, N₂ inlet, and gas adapter connected to a bubblerwas charged with palladium acetate (12.8 g), tri-o-tolylphosphine (69.9g), and N,N-dimethylformamide (DMF) (2.8 L). N₂ was bubbled through thesolution for 20 min at ambient temperature. The flask was then heated to56° C. on a heating mantle, and the mixture was stirred at 60° C. for 20min. A solution of diethylzinc in toluene (1.1M, 78.0 mL) was added viasyringe. The resulting suspension was stirred at 56° C. for 45 min.

Cyanation Reaction:

A 4-neck 12 L flask equipped with a mechanical stirrer, thermocouple,nitrogen inlet, and gas adapter connected to a bubbler was charged with3-(3-bromophenyl)-4-(4-chlorophenyl)butan-2-one (3), zinc cyanide (201g), and N,N-dimethylformamide (4.0 L). Nitrogen gas was bubbled throughthe suspension for 30 min at room temperature and for 1 h at 56° C.using a heating mantle. The bromoketone/Zn(CN)₂ slurry (at 56° C.) wasadded to the catalyst solution (at 56° C.). After the transfer wascomplete, the reaction mixture was stirred at 56° C. for 4.5 h under N₂.The resulting suspension was cooled in an ice bath, and 30% aqueousammonium hydroxide (971 mL) was added over 5 min, keeping thetemperature below 30° C. The suspension was warmed to room temperature,stirred for 60 min, and then filtered through a pad of SOLKA FLOCeluting with toluene (5 L). The filtrate was added into an extractorcontaining 20% aqueous ammonium hydroxide (6.9 L) and 5 L of toluene.The biphasic mixture was stirred at room temperature for 15 min and thenseparated. The organic layer was washed with 7 L of brine (1:1 saturatedNaCl:water), then 7 L of water. The organic phase was transferred to a12-L 4-neck flask equipped with an overhead stirrer, thermocouple,mechanical stirrer, and connected to a batch concentrator. The batch wasconcentrated under vacuum at 15-38° C. to a volume of 1.5 L, and thenheptane (850 mL) was added. A sample was taken at this point, andcrystallized in a vial. This seed sample was recharged back to the flaskwhich created a seed bed for the crystallization. Once a seed bed formed(about 30 min), 6.5 L of heptane was added over 40 min, and the batchwas cooled to 0° C. The batch was filtered, and the filter cake waswashed with heptane (2 L). The resulting solid was dried under a streamof nitrogen to provide the title compound.

Step C:3-(4-chlorophenyl)-2-(3-cyanophenyl-1-methylprop-1-en-1-yl4-methylbenzenesulfonate(5)

A 4-neck, 12 L flask equipped with a mechanical stirrer, thermocouple,and nitrogen inlet was charged N,N-dimethylacetamide (7.2 L), followedby 3 [1-(4-chlorobenzyl)-2-oxopropyl]benzonitrile (4, 744 g), thenbubbled with nitrogen through the reaction mixture for 30 min at roomtemperature. The mixture was cooled to −10° C., and NaOtBu (265 g) wasadded as a solid in one portion with stirring (tmax=−2° C.). Thesolution was allowed to stir with cooling until the exotherm stopped andthe temperature began to drop (about 2 min). The cooling bath wasremoved, and the reaction was warmed to room temperature, then stirredfor 1 h. The mixture was cooled to −20° C. and p-toluenesulfonicanhydride (Ts₂O, 893 g) was added as a solid in two portions withstirring, keeping the temperature below −5° C. (tmax=−8° C.). Themixture was allowed to cool back to −10° C. and stirred for 1 h. Thereaction was quenched with 1 M NaHCO₃ (1.9 L), and transferred to a 50 Lextractor containing 15 L IPAc and 13 L water. The layers were separatedand the organic layer was washed twice with 7.5 L water. The organiclayer was concentrated under slight vacuum (25 in Hg) at 55° C. to about2 L. Upon reaching the 2 L volume, the batch began to crystallize, sothe vacuum was turned off and the flask was heated to 73° C. to producea homogeneous solution. Heptane (6.6 L) was added while the mixture wasallowed to slowly cool to room temperature. The resulting slurry wasaged for 1 h at room temperature, then filtered. The filter cake waswashed with 3 L heptane and dried under a stream of nitrogen to yieldthe title compound.

Step D:N-[(1Z)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylprop-1-en-1-yl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide(6)

A 3-neck 3 L round bottom flask was charged with tert-amyl alcohol (2.4L). Nitrogen gas was bubbled through the solution for 2 h. A 3-neck 5 Lround bottom flask fitted with a mechanical stirrer, reflux condenser,and a nitrogen/vacuum adapter on top of the reflux condenser was chargedwith Pd₂dba₃ (27.5 g), 1,4-bis(diphenylphosphino)butane (51.2 g),2-methyl-2-{[5-(trifluoromethyl)pyridine-2-yl]oxy}propanamide (2, 313g),3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylprop-1-en-1-yl4-methylbenzenesulfonate(5, 526 g), and potassium carbonate (332 g). The flask was sealed,evacuated, and backfilled with nitrogen. Tert-amyl alcohol (2.4 L) wasadded to the reaction flask followed by heating to 100° C. and stirringat 100° C. for 18 h. The resulting suspension was cooled to 25° C. andtransferred into a 4-necked 22 L round bottom flask equipped with amechanical stirrer. The batch was diluted with 7.2 L of MTBE, then DARCOKB-B® (250 g) was charged to the mixture. The resulting mixture wasstirred for 2 h at RT, then filtered over a pad of SOLKA FLOC. Thefilter cake was washed with 7 L of MTBE. The batch was vacuumtransferred to a 4-necked 12 L round bottom flask equipped with anoverhead stirrer and thermocouple. The batch was concentrated at 10-20°C. to remove all the MTBE and then at 30-40° C. to reduce the volume ofthe remaining t-amyl alcohol to ˜1.5 L. Heptane (5 L) was added over ˜30minutes and the batch was cooled to 20° C. The filter cake was washedwith 2 L of heptane-MTBE (10:1) and dried under a stream of nitrogen toprovide the title compound.

Step E:3-{(1Z)-1-(4-chlorobenzyl)-2-[(2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoyl)amino]-prop-1-en-1-yl}benzamide(7)

To a 5 L, 3-necked round bottom flask equipped with overhead stirrer,thermocouple, and nitrogen inlet was added 524 g of the cyano enamide 6and 112 g K₂CO₃. DMSO (2.7 L) was charged and the vessel was submergedin a RT water bath. Hydrogen peroxide solution (165 mL of a 30% aqueoussolution) was slowly added to the reactor such that the temperaturenever rose above 25° C. After the addition was complete, the reactionwas aged for 1 h. The batch was diluted with 1 L of isopropyl acetateand filtered over a bed of SOLKA FLOC. The bed was washed with 4.5 L ofisopropyl acetate and the resulting solution was transferred to a 50 Lextractor containing 5.5 L of water. The layers were separated and theorganic layer was washed twice with 3.1 L of water, concentrated to 5 L,and solvent switched to 5 L toluene at about 60° C. Upon completion ofthe solvent switch, 500 mL of heptane was added and the mixture wascooled to 20° C. The batch was aged for 30 min at 20° C., then filteredand washed with 1 L of toluene. The resulting solid was dried overnightunder a stream of nitrogen to afford the title compound.

Step F:3-{(1S,2S)-1-(4-chlorobenzyl)-2-[(2-methyl-2-{[5-(trifluoromethylpyridine-2-yl]oxy}propanoyl)amino]-propyl}benzamide(8)

Catalyst Preparation:

In a N₂-filled glove box, 2.83 g (−)-TMBTP was added to a 0.5 L bottlecontaining a stir bar. (COD)₂Rh BF₄ (1.85 g) was added to the samebottle and then methanol (360 mL) was added. The resulting solution wasaged with stirring for 1 h. BF₃—MeOH (41.2 g, 12 wt % in MeOH, 4.94 gBF₃) was added to the catalyst solution, and the resulting mixture wasadded to a 1-L stainless steel bomb. 50 mL of MeOH was used to rinse themixture into the bomb. Isopropanol (200 mL) was charged to the rinsechamber of the bomb, and then each chamber of the bomb was sealed beforeremoving it from the glove box.

Hydrogenation:

Compound 7 was charged to a 5 L bottle, and isopropanol (3.3 L) wasadded to the bottle to create a slurry. The resulting slurry wastransferred by vacuum through a polyethylene line into a 2 gallonstainless steel autoclave. The 5-L bottle was rinsed with 1 L ofisopropanol and the rinse was also transferred into the 2 gallonautoclave. The autoclave was degassed five times with N₂, and thenplaced under partial vacuum. The catalyst bomb was connected to theautoclave via flexible polyethylene tubing (flushed with N₂) and thecatalyst solution was drawn into the autoclave followed by theisopropanol wash from the rinse chamber. The autoclave was sealed,degassed with N₂ purges three times and pressurized up to 150 psi. Thestirrer was initiated, and the temperature was raised to 40° C. Thereaction was aged at 150 psi, 40° C. for 18 h. The temperature wasdropped to room temperature, and the resulting solution was transferredto a polyethylene jug.

Step G:N-[1S,2S]-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide(9)

The crude hydrogenation solution from Step F was solvent switched from 4L isopropanol to ˜1 L DMF (40° C., 30 mm Hg). The resulting solution of470 g of intermediate 8 in DMF was transferred to a 12 L 4-necked roundbottom flask equipped with mechanical stirrer, thermocouple, and 2 Laddition funnel. Cyanuric chloride (103 g) was slurried in 2 L of MTBEand the resulting slurry was charged to the reaction via the 2 Laddition funnel over about 10 min. The reaction mixture was aged withstirring for 1 h. The batch was cooled to 10° C. and diluted with 3 L ofMTBE. 2 L of water and 2 L of saturated NaHCO₃ solution were added tothe reaction while keeping the temperature below 20° C. The resultingslurry was transferred to a 50 L extractor containing 3 L of MTBE, 3 Lof water, and 3 L of saturated aqueous NaHCO₃. An additional 12 L ofwater was added to the batch and the layers were allowed to settle. Theorganic layer was washed twice with 3 L of water. The organic layer wasazeotroped at 35° C., 17 in Hg to bring the KF to 219 (spec. at 500)while maintaining a volume of about 11 L. The batch was then treatedwith 320 g of ECOSORB C941. The batch was aged for 4 h at 50° C., thenfiltered over a pad of SOLKA FLOC and washed with 6 L of MTBE. Theresulting filtrate was recharged to a 22 L vessel, concentrated to 11 Lvolume, and retreated with 116 g of ECOSORB C941. This slurry wasfiltered over a bed of SOLKA FLOC, and washed with 6 L MTBE. Theresulting colorless MTBE layer was transferred through a 1 micron inlinefilter into a 12 L, 4 neck round bottom flask equipped with overheadstirrer and thermocouple, and concentrated to about 2 L volume at 17 inHg, 35° C. The batch was cooled to room temperature, and a sample wasremoved to create a seed bed. Once the sample crystallized, it wasreturned to the flask, and the batch was aged for 30 minutes, creating alarge seed bed. The isolated solid was dried over a stream of nitrogento afford the title compound as a hemisolvate.

The DPP-IV inhibitors including the compound of structural formula IVfor use in the compositions of the present invention were prepared asdescribed in U.S. Pat. No. 6,699,871, the contents of which areincorporated herein by reference in their entirety. Thedihydrogenphosphate salt of structural formula V and its crystallinemonohydrate form were prepared as described below.

(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo-4,3-α]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-aminedihydrogenphosphate monohydrate (MK-0431) Preparation of3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-α]pyrazinehydrochloride (1-4)

Step A: Preparation of bishydrazide (1-1)

Hydrazine (20.1 g, 35 wt % in water, 0.22 mol) was mixed with 310 mL ofacetonitrile. 31.5 g of ethyl trifluoroacetate (0.22 mol) was added over60 min. The internal temperature was increased to 25° C. from 14° C. Theresulting solution was aged at 22-25° C. for 60 min. The solution wascooled to 7° C. 17.9 g of 50 wt % aqueous NaOH (0.22 mol) and 25.3 g ofchloroacetyl chloride (0.22 mol) were added simultaneously over 130 minat a temperature below 16° C. When the reaction was complete, themixture was vacuum distilled to remove water and ethanol at 27˜30° C.and under 26˜27 in Hg vacuum. During the distillation, 720 mL ofacetonitrile was added slowly to maintain constant volume (approximately500 mL). The slurry was filtered to remove sodium chloride. The cake wasrinsed with about 100 mL of acetonitrile. Removal of the solventafforded bis-hydrazide 1-1.

¹H-NMR (400 MHz, DMSO-d₆): δ 4.2 (s, 2H), 10.7 (s, 1H), and 11.6 (s, 1H)ppm.

¹³C-NMR (100 MHz, DMSO-d₆): δ 41.0, 116.1 (q, J=362 Hz), 155.8 (q, J=50Hz), and 165.4 ppm.

Step B: Preparation of5-(trifluoromethyl)-2-(chloromethyl)-1,3,4-oxadiazole (1-2)

Bishydrazide 1-1 from Step A (43.2 g, 0.21 mol) in ACN (82 mL) wascooled to 5° C. Phosphorus oxychloride (32.2 g, 0.21 mol) was added,maintaining the temperature below 10° C. The mixture was heated to 80°C. and aged at this temperature for 24 h until HPLC showed less than 2area % of 1-1. In a separate vessel, 260 mL of IPAc and 250 mL of waterwere mixed and cooled to 0° C. The reaction slurry was charged to thequench keeping the internal temperature below 10° C. After the addition,the mixture was agitated vigorously for 30 min, the temperature wasincreased to room temperature and the aqueous layer was cut. The organiclayer was then washed with 215 mL of water, 215 mL of 5 wt % aqueoussodium bicarbonate and finally 215 mL of 20 wt % aqueous brine solution.HPLC assay yield after work up was 86-92%. Volatiles were removed bydistillation at 75-80 mm Hg, 55° C. to afford an oil which could be useddirectly in Step C without further purification. Otherwise the productcan be purified by distillation to afford 1-2.

¹H-NMR (400 MHz, CDCl₃): δ 4.8 (s, 2H) ppm.

¹³C-NMR (100 MHz, CDCl₃): δ 32.1, 115.8 (q, J=337 Hz), 156.2 (q, J=50Hz), and 164.4 ppm.

Step C: Preparation ofN-[(2Z)-piperazin-2-ylidene]trifluoroacetohydrazide (1-3)

To a solution of ethylenediamine (33.1 g, 0.55 mol) in methanol (150 mL)cooled at −20° C. was added distilled oxadiazole 1-2 from Step B (29.8g, 0.16 mol) while keeping the internal temperature at −20° C. After theaddition was complete, the resulting slurry was aged at −20° C. for 1 h.Ethanol (225 mL) was then charged and the slurry slowly warmed to −5° C.After 60 min at −5° C., the slurry was filtered and washed with ethanol(60 mL) at −5° C. Amidine 1-3 was obtained as a white solid (24.4 g,99.5 area wt % pure by HPLC).

¹H-NMR (400 MHz, DMSO-d₆): δ 2.9 (t, 2H), 3.2 (t, 2H), 3.6 (s, 2H), and8.3 (b, 1H) ppm. ¹³C-NMR (100 MHz, DMSO-d₆): δ 40.8, 42.0, 43.3, 119.3(q, J=350 Hz), 154.2, and 156.2 (q, J=38 Hz) ppm.

Step D: Preparation of3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-α]pyrazinehydrochloride (14) A suspension of amidine 1-3 (27.3 g, 0.13 mol) in 110mL of methanol was warmed to 55° C. 37% Hydrochloric acid (11.2 mL, 0.14mol) was added over 15 min at this temperature. During the addition, allsolids dissolved resulting in a clear solution. The reaction was agedfor 30 min. The solution was cooled down to 20° C. and aged at thistemperature until a seed bed formed (10 min to 1 h). 300 mL of MTBE wascharged at 20° C. over 1 h. The resulting slurry was cooled to 2° C.,aged for 30 min and filtered. Solids were washed with 50 mL ofethanol:MTBE (1:3) and dried under vacuum at 45° C.

¹H-NMR (400 MHz, DMSO-d₆): δ 3.6 (t, 2H), 4.4 (t, 2H), 4.6 (s, 2H), and10.6 (b, 2H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ 39.4, 39.6, 41.0, 118.6(q, J=325 Hz), 142.9 (q, J=50 Hz), and 148.8 ppm.

Step A: Preparation of4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-1-(2,4,5-trifluorophenyl)butan-2-one(2-3)

2,4,5-Trifluorophenylacetic acid (2-1) (150 g, 0.789 mol), Meldrum'sacid (125 g, 0.868 mol), and 4-(dimethylamino)pyridine (DMAP) (7.7 g,0063 mol) were charged into a 5 L three-neck flask N,N-Dimethylacetamide(DMAc) (525 mL) was added in one portion at room temperature to dissolvethe solids. N,N-diisopropylethylamine (282 mL, 1.62 mol) was added inone portion at room temperature while maintaining the temperature below40° C. Pivaloyl chloride (107 mL, 0.868 mol) was added dropwise over 1to 2 h while maintaining the temperature between 0 and 5° C. Thereaction mixture was aged at 5° C. for 1 h. Triazole hydrochloride 1-4(180 g, 0.789 mol) was added in one portion at 40-50° C. The reactionsolution was aged at 70° C. for several h. 5% Aqueous sodiumhydrogencarbonate solution (625 mL) was then added dropwise at 20-45° C.The batch was seeded and aged at 20-30° C. for 1-2 h. Then an additional525 mL of 5% aqueous sodium hydrogencarbonate solution was addeddropwise over 2-3 h. After aging several h at room temperature, theslurry was cooled to 0-5° C. and aged 1 h before filtering the solid.The wet cake was displacement-washed with 20% aqueous DMAc (300 mL),followed by an additional two batches of 20% aqueous DMAc (400 mL), andfinally water (400 mL). The cake was suction-dried at room temperature.

Step B: Preparation of(2Z)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine(2-4)

A 5 L round-bottom flask was charged with methanol (100 mL), theketoamide 2-3 (200 g), and ammonium acetate (110.4 g). Methanol (180 mL)and 28% aqueous ammonium hydroxide (58.6 mL) were then added keeping thetemperature below 30° C. during the addition. Additional methanol (100mL) was added to the reaction mixture. The mixture was heated at refluxtemperature and aged for 2 h. The reaction was cooled to roomtemperature and then to about 5° C. in an ice-bath. After 30 min, thesolid was filtered and dried to afford 2-4 as a solid; m.p. 271.2° C.

Step C: Preparation of(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine(2-5)

Into a 500 ml flask were charged chloro(1,5-cyclooctadiene)rhodium(I)dimer {[Rh(cod)Cl]₂} (292 mg, 1.18 mmol) and (R,S) t-butyl Josiphos (708mg, 1.3 mmol) under a nitrogen atmosphere. Degassed MeOH was then added(200 mL) and the mixture was stirred at room temperature for 1 h. Into a4 L hydrogenator was charged the enamine amide 2-4 (118 g, 0.29 mol)along with MeOH (1 L). The slurry was degassed. The catalyst solutionwas then transferred to the hydrogenator under nitrogen. After degassingthree times, the enamine amide was hydrogenated under 200 psi hydrogengas at 50° C. for 13 h. Assay yield was determined by HPLC to be 93% andoptical purity to be 94% ee.

The optical purity was further enhanced in the following manner. Themethanol solution from the hydrogenation reaction (18 g in 180 mL MeOH)was concentrated and switched to methyl t-butyl ether (MTBE) (45 mL).Into this solution was added aqueous H₃PO₄ solution (0.5 M, 95 mL).After separation of the layers, 3N NaOH (35 mL) was added to the waterlayer, which was then extracted with MTBE (180 mL+100 mL). The MTBEsolution was concentrated and solvent switched to hot toluene (180 mL,about 75° C.). The hot toluene solution was then allowed to cool to 0°C. slowly (5-10 h). The crystals were isolated by filtration (13 g,yield 72%, 98-99% ee); m.p. 114.1-115.7° C.

¹H NMR (300 MHz, CD₃CN): δ 7.26 (m), 7.08 (m), 4.90 (s), 4.89 (s), 4.14(m), 3.95 (m), 3.40 (m), 2.68 (m), 2.49 (m), 1.40 (bs).

Compound 2-5 exists as amide bond rotamers. Unless indicated, the majorand minor rotamers are grouped together since the carbon-13 signals arenot well resolved:

¹³C NMR (CD₃CN): δ 171.8, 157.4 (ddd, J_(CF)=242.4, 9.2, 2.5 Hz), 152.2(major), 151.8 (minor), 149.3 (ddd; J_(CF)=246.7, 14.2, 12.9 Hz), 147.4(ddd, J_(CF)=241.2, 12.3, 3.7 Hz), 144.2 (q, J_(CF)=38.8 Hz), 124.6(ddd, J_(CF)=18.5, 5.9, 4.0 Hz), 120.4 (dd, J_(CF)=19.1, 6.2 Hz), 119.8(q, J_(CF)=268.9 Hz), 106.2 (dd, J_(CF)=29.5, 20.9 Hz), 50.1, 44.8, 44.3(minor), 43.2 (minor), 42.4, 41.6 (minor), 41.4, 39.6, 38.5 (minor),36.9.

The crystalline free base can also be isolated as follows:

-   (a) The reaction mixture upon completion of the hydrogenation step    is charged with 25 wt % of Ecosorb C-941. The mixture is stirred    under nitrogen for one h and then filtered. The cake is washed with    2 L/kg of methanol. Recovery of free base is about 95% and optical    purity about 95% ee.-   (b) The freebase solution in methanol is concentrated to 3.5-4.0    L/kg volume (based on free base charge) and then solvent-switched    into isopropanol (IPA) to final volume of 3.0 L/kg IPA.-   (c) The slurry is heated to 40° C. and aged 1 h at 40° C. and then    cooled to 25° C. over 2 h.-   (d) Heptane (7 L/kg) is charged over 7 h and the slurry stirred for    12 h at 22-25° C. The supernatant concentration before filtering is    10-12 mg/g.-   (e) The slurry is filtered and the solid washed with 30% IPA/heptane    (2 L/kg).-   (f) The solid is dried in a vacuum oven at 40° C.-   (g) The optical purity of the free base is about 99% ee.

(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-aminedihydrogenphosphate monohydrate (MK-0431)

A 250 mL round bottom flask equipped with an overhead stirrer, heatingmantle and thermocouple, was charged with 31.5 mL of isopropanol (IPA),13.5 mL water, 15.0 g (36.9 mmol) of(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-aminefreebase and 4.25 g (36.9 mmol) of 85% aqueous phosphoric acid. Themixture was heated to 75° C. A thick white precipitate formed at lowertemperatures but dissolved upon reaching 75° C. The solution was cooledto 68° C. and then held at that temperature for 2 h. A slurry bed ofsolids formed during this age time [the solution can be seeded with 0.5to 5 wt % of small particle size (alpine milled) monohydrate]. Theslurry was then cooled at a rate of 4° C./h to 21° C. and then heldovernight. 105 mL of IPA was then added to the slurry. After 1 h theslurry was filtered and washed with 45 mL IPA (solids can also be washedwith a water/IPA solution to avoid turnover to other crystal forms). Thesolids were dried on the frit with open to air. 18.6 g of solids wererecovered. The solids were found to greater than 99.8% pure by HPLC areapercentage (HPLC conditions same as those given above). The particlesize distribution analysis of the isolated solids showed a mean PSD of80 microns with 95% less than 180 microns. The crystal form of thesolids was shown to be monohydrate by X-ray powder diffraction andthermogravimetric analysis.

EXAMPLE 1 In Vivo Study for Combination Therapy with a DPP-IV Inhibitor(Mk-0431) and a Cannabinoid CB₁ Receptor Antagonist/Inverse Agonist(Compound of Formula III) (Effect on Obesity/Food Intake andGlucose/Insulin)

DIO mice are treated simultaneously with an effective dose of Compoundof Formula III and an effective dose of MK-0431.

Materials and Methods:

Male C57BL/6J mice (CLEA Japan Inc., 12-16 months old at the beginningof the drug administration) are used. Mice are given water and regularpellet chow (CE-2, CLEA Japan Inc.) ad libitum. They are kept in ananimal room which is maintained at 23±2° C. temperature, 55±15% relativehumidity and on a 12-hr light-dark cycle (7:00-19:00) during aquarantine and acclimatization period of 1 week. Before the start ofdrug administration, mice are fed a MHF diet (Oriental BioService Co.,Tokyo, Japan) for at least 2 months until the body weight gain reaches aplateau. After the body weight gain reaches a plateau, the diet ischanged to a powder MHF diet. The powder MHF diet is given by powderfeeder (small dishes). Diet and dishes are changed everyday, and dailyfood intake is measured. During this period, animals are orallyadministered vehicle (0.5% methylcellulose in distilled water) by gavageonce-daily. After the stable feeding is observed, the amount of new foodis adjusted to daily food intake+0.3 g, to minimize the amount ofspilled food. After the acclimation period, the MHF diet-fed mice aredivided into two groups to match average values of body weight and foodintake (n=8-12). One of the groups is orally administered vehicle whilethe second group is administered a combination of Compound of FormulaIII and MK-0431. MK-0431 is given at a dose of 100 mg/kg once-daily andCompound of Formula III is given at a dose of 10 mg/kg once a day for1.5 months by gavage, respectively. The administration is done one andhalf hours before the beginning of the dark period following themeasurement of body weight. Food and body weight are measured. At theend of the treatment period, animals are fasted overnight and an oralglucose tolerance test is performed.

Effective combinations result in body weight loss of >5% and astatistically significant reduction in glucose and/or insulin, and/orimprovement in an oral glucose tolerance test in the treated groupcompared to the vehicle treated group.

EXAMPLE 2 Human Study for Combination Therapy with a DPP-IV Inhibitor(Mk-0431) and a Cannabinoid CB₁ Receptor Antagonist/Inverse Agonist(Compound of Formula III) (Effect on Obesity/Food Intake andGlucose/Insulin) Materials and Methods:

A suitable number of people with a BMI≧30 who have impaired fastingplasma glucose levels, impaired glucose tolerance, or elevated seruminsulin, indicative of a prediabetic insulin resistant state, or who mayhave elevated serum glucose levels, indicative of type II diabetes, areadvised to diet and increase their physical activity. After a two-weekplacebo run-in period, which includes a standardized program of diet,physical activity, and lifestyle changes, the patients are randomizedinto 4 treatment groups: placebo; an effective dose of MK-0431, such as100 mg; an effective dose of Compound of Formula III, such as 10 mg; andan effective dose of Compound of Formula III plus an effective dose ofMK-0431. Compound of Formula III is given once or more per day, aspreviously determined to be effective. MK-0431 is given once or more perday, as previously determined to be effective. The two compounds may begiven in a single dosage form. Patients are treated for 6 months, bodyweights are measured every two to four weeks, and appetite, hunger,satiety are measured every two to twelve weeks using standardquestionnaires. Serum glucose and insulin levels are determined at day0, at four to twelve week intervals, and after the final dose.

Effective combinations result in body weight loss of ≧5% and animprovement in serum insulin levels, indicative of improved insulinsensitivity and/or lower fasting blood glucose levels.

EXAMPLE 3 Non Diabetic Rodent Model of Metabolic Syndrome: Study forCombination Therapy with a DPP-IV Inhibitor (Mk-0431) and a CannabinoidCB₁ Receptor Antagonist/Inverse Agonist (Compound of Formula III)Optionally Containing an Anti-Hypersensitive Agent and/or anAnti-Dyslipidemic Agent. (Effect Blood Pressure, Serum Insulin Levels,Triglyceride Levels, and Fatty Acid Levels)

The following experiment demonstrates the ability of the composition tolower blood pressure in an animal model of Metabolic Syndrome. Thisexperiment uses a non-diabetic rodent model where blood insulin levels,blood pressure and serum triglycerides are elevated but serum glucoselevels are within normal limits.

Materials and Methods

Male, Sprague-Dawley rats Harlan Sprague Dawley, Indianapolis, Ind.),initially weighing 175-199 g are used for all experiments. Prior todietary manipulation, all rats are fed Purina Rat Chow (no. 5012; St.Louis, Mo.) and water ad libitum and maintained on a 12-h (0600-1800 h)light-dark cycle. The rats are then placed on a diet (TD 78463; HarlanTeklad, Madison, Wis.) which provides 60% of total calories as fructose.The fructose-enriched diet is given for 11 days, during which time therats are acclimated to the procedure of blood pressure measurement.Ambient temperature is kept at 30 C. The equipment used includesmagnetic animal holders connected with manual scanner (model 65-12,IITC, Inc., Woodland Hills, Calif.), pulse amplifier (model 59, IITC,Inc.), and dual-channel recorder (model 1202, Linear Intrs. Corp., Reno,Nev.).

At the end of the initial dietary period, blood pressure is determined,and rats randomly divided into two groups. Both groups are maintained onthe fructose-enriched diet, but one group is gavaged with a combinationof MK-0431 (such as 100 mpk PO) and Compound of Formula III, optionallywith an antihypertensive agent such as enalapril or losartan and/or ananti-lipid agent such as simvastatin, whereas the other group is treatedin the same manner with vehicle alone. Blood pressure is measured onceper week, before and after doses of either the combination or vehicle (8weeks of treatment). In both instances, the general procedure issimilar. Rats are removed from the animal room and taken to thelaboratory at 0900 h. They are allowed free access to water and are keptin a quiet area before the blood pressure is measured at 1300 h. Thetail-cuff method, without external preheating, is used to measure thesystolic blood pressure. The systolic blood pressure is measured in theconscious state and has been shown with this technique to be similar tothat obtained by direct arterial cannulation. The final blood pressuredeterminations were performed on the afternoon following the lastmorning dose of the combination or vehicle. In approximately half of therats studied, tail vein blood is removed at 1300 h (four hours afterremoval of food), centrifuged, frozen, and later assayed for plasmaglucose, insulin, and triglyceride concentrations. Plasma free fattyacid concentration is assayed enzymatically by the ACS-ACOD method usinga commercial kit (Waro Chemicals Inc., Richmond, Va.).

The animal model used in this example has many of the features ofMetabolic Syndrome. Fructose fed rats do not have increased bloodglucose and therefore this is not a diabetic model. However, these ratsdo show increased serum insulin, increased triglycerides and free fattyacid concentration and increased blood pressure. Thus, this animal modelis the animal model for Metabolic Syndrome.

Effective compositions improve the characteristic cluster of symptomsassociated with Metabolic Syndrome. Effective compositions lower atleast two of the symptoms of Metabolic Syndrome: blood pressure, bloodinsulin, free fatty acid, bodyweight and triglyceride levels in anon-diabetic rat model where blood glucose levels remain normal.

Additional animal models can be used, including BRS3 KO mice(Ohki-Hamazki et al, Nature 390: 165 (1997) and diet-induced obese andhypertensive dogs (Hall et al, Am. J. Hypertension. 14: 103S-115S(2001)).

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inresponsiveness of the mammal being treated for any of the indicationswith the compounds of the invention indicated above. The specificpharmacological responses observed may vary according to and dependingupon the particular active compounds selected or whether there arepresent pharmaceutical carriers, as well as the type of formulation andmode of administration employed, and such expected variations ordifferences in the results are contemplated in accordance with theobjects and practices of the present invention. It is intended,therefore, that the invention be defined by the scope of the claimswhich follow and that such claims be interpreted as broadly as isreasonable.

1. A pharmaceutical composition comprising a cannabinoid CB₁ receptorantagonist/inverse agonist selected from the group consisting of:N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;N-[3-(4-chlorophenyl)-1-methyl-2-phenyl-propyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;N-[3-(4-chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide;N-[3-(4-chlorophenyl)-1-methyl-2-(thiophen-3-yl)propyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;N-[3-(5-chloro-2-pyridyl)-2-phenyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;N-[3-(4-fluorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;N-[3-(4-methoxy-phenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;N-[2-(3-cyanophenyl)-1,4-dimethylpentyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;N-[2-(3-cyanophenyl)-3-cyclobutyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;N-[2-(3-cyanophenyl)-1-methyl-heptyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;N-[2-(3-cyanophenyl)-3-cyclopentyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;N-[2-(3-cyanophenyl)-3-cyclohexyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;3-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-3-(3,5-difluorophenyl)-2,2-dimethylpropanenitrile;1-{1-[1-(4-chlorophenyl)pentyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol;3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile;3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile;3-((4-chlorophenyl){3-[1-(3,5-difluorophenyl)-2,2-dimethylpropyl]azetidin-1-yl}methyl)benzonitrile;3-((1S)-1-{1-[(S)-(3-cyanophenyl)(4-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile;3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(4H-1,2,4-triazol-4-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile;and5-((4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)thiophene-3-carbonitrile;or a stereoisomer, pharmaceutically acceptable salt, hydrate, andcrystalline form thereof; and a dipeptidyl peptidase-IV inhibitor whichis(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amineof the structural formula:

or a pharmaceutically acceptable salt, hydrate, and crystalline formthereof.
 2. The pharmaceutical composition of claim 1 wherein saidpharmaceutically acceptable salt of said dipeptidyl peptidase-IVinhibitor is the dihydrogenphosphate salt of the structural formula:

or a pharmaceutically acceptable hydrate thereof.
 3. The pharmaceuticalcomposition of claim 2 wherein said CB₁ receptor antagonist/inverseagonist isN-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamideof the formula:

or a pharmaceutically acceptable salt, hydrate, or crystalline formthereof.
 4. The pharmaceutical composition of claim 3 wherein saiddihydrogenphosphate salt is in the form of a crystalline monohydrate. 5.A method of treating a condition selected from diabetes, adiabetes-related disorder, obesity, and an obesity-related disordercomprising administering to a subject in need thereof a therapeuticallyeffective amount of the composition of claim
 3. 6. The method of claim 5wherein said dihydrogenphosphate salt is in the form of a crystallinemonohydrate.
 7. The method of claim 5 wherein said condition isdiabetes.
 8. The method of claim 5 wherein said condition is obesity. 9.The method of claim 5 wherein said diabetes-related disorder is selectedfrom the group consisting of hyperglycemia, prediabetes, impairedglucose tolerance, impaired fasting glucose, obesity, dyslipidemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDLlevels, high LDL levels, atherosclerosis, hypertension, sleep apnea,polycystic ovarian syndrome, and Metabolic Syndrome. 10-11. (canceled)12. The method of claim 5 wherein said cannabinoid CB₁ receptorantagonist/inverse agonist and said dipeptidyl peptidase-IV inhibitorare administered together in a single pharmaceutical composition inassociation with a pharmaceutically acceptable carrier or diluent.